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1.  Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8+ Cells 
The role of chemokines in the pathogenesis of lung cancer has been increasingly appreciated. Monocyte chemoattractant protein–1 (MCP-1, also known as CCL2) is secreted from tumor cells and associated tumor stromal cells. The blockade of CCL2, as mediated by neutralizing antibodies, was shown to reduce tumorigenesis in several solid tumors, but the role of CCL2 in lung cancer remains controversial, with evidence of both protumorigenic and antitumorigenic effects. We evaluated the effects and mechanisms of CCL2 blockade in several animal models of non–small-cell lung cancer (NSCLC). Anti-murine–CCL2 monoclonal antibodies were administered in syngeneic flank and orthotopic models of NSCLC. CCL2 blockade significantly slowed the growth of primary tumors in all models studied, and inhibited lung metastases in a model of spontaneous lung metastases of NSCLC. In contrast to expectations, no significant effect of treatment was evident in the number of tumor-associated macrophages recruited into the tumor after CCL2 blockade. However, a change occurred in the polarization of tumor-associated macrophages to a more antitumor phenotype after CCL2 blockade. This was associated with the activation of cytotoxic CD8+ T lymphocytes (CTLs). The antitumor effects of CCL2 blockade were completely lost in CB-17 severe combined immunodeficient mice or after CD8 T-cell depletion. Our data from NSCLC models show that CCL2 blockade can inhibit the tumor growth of primary and metastatic disease. The mechanisms of CCL2 blockade include an alteration of the tumor macrophage phenotype and the activation of CTLs. Our work supports further evaluation of CCL2 blockade in thoracic malignancies.
doi:10.1165/rcmb.2010-0080OC
PMCID: PMC3049234  PMID: 20395632
tumor immunology; CCL2; lung cancer; mesothelioma; tumor-associated macrophages
2.  A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells 
Cell Research  2012;23(3):394-408.
CCL5 is a member of the CC chemokine family expressed in a wide array of immune and non-immune cells in response to stress signals. CCL5 expression correlates with advanced human breast cancer. However, its functional significance and mode of action have not been established. Here, we show that CCL5-deficient mice are resistant to highly aggressive, triple-negative mammary tumor growth. Hematopoietic CCL5 is dominant in this phenotype. The absence of hematopoietic CCL5 causes aberrant generation of CD11b+/Gr-1+, myeloid-derived suppressor cells (MDSCs) in the bone marrow in response to tumor growth by accumulating Ly6Chi and Ly6G+ MDSCs with impaired capacity to suppress cytotoxicity of CD8+ T cells. These properties of CCL5 are observed in both orthotopic and spontaneous mammary tumors. Antibody-mediated systemic blockade of CCL5 inhibits tumor progression and enhances the efficacy of therapeutic vaccination against non-immunogenic tumors. CCL5 also helps maintain the immunosuppressive capacity of human MDSCs. Our study uncovers a novel, chemokine-independent activity of the hematopoietically derived CCL5 that promotes mammary tumor progression via generating MDSCs in the bone marrow in cooperation with tumor-derived colony-stimulating factors. The study sheds considerable light on the interplay between the hematopoietic compartment and tumor niche. Because of the apparent dispensable nature of this molecule in normal physiology, CCL5 may represent an excellent therapeutic target in immunotherapy for breast cancer as well as a broad range of solid tumors that have significant amounts of MDSC infiltration.
doi:10.1038/cr.2012.178
PMCID: PMC3587709  PMID: 23266888
CCL5; myeloid-derived suppressor cell; triple-negative breast cancer; immune response; mammary tumor; bone marrow; cytotoxic T lymphocyte
3.  Co-Introduced Functional CCR2 Potentiates In Vivo Anti-Lung Cancer Functionality Mediated by T Cells Double Gene-Modified to Express WT1-Specific T-Cell Receptor 
PLoS ONE  2013;8(2):e56820.
Background and Purpose
Although gene-modification of T cells to express tumor-related antigen-specific T-cell receptor (TCR) or chimeric antigen receptor (CAR) has clinically proved promise, there still remains room to improve the clinical efficacy of re-directed T-cell based antitumor adoptive therapy. In order to achieve more objective clinical responses using ex vivo-expanded tumor-responsive T cells, the infused T cells need to show adequate localized infiltration into the tumor.
Methodology/Principal Findings
Human lung cancer cells variously express a tumor antigen, Wilms' Tumor gene product 1 (WT1), and an inflammatory chemokine, CCL2. However, CCR2, the relevant receptor for CCL2, is rarely expressed on activated T-lymphocytes. A HLA-A2402+ human lung cancer cell line, LK79, which expresses high amounts of both CCL2 and WT1 mRNA, was employed as a target. Normal CD8+ T cells were retrovirally gene-modified to express both CCR2 and HLA-A*2402-restricted and WT1235–243 nonapeptide-specific TCR as an effector. Anti-tumor functionality mediated by these effector cells against LK79 cells was assessed both in vitro and in vivo. Finally the impact of CCL2 on WT1 epitope-responsive TCR signaling mediated by the effector cells was studied. Introduced CCR2 was functionally validated using gene-modified Jurkat cells and human CD3+ T cells both in vitro and in vivo. Double gene-modified CD3+ T cells successfully demonstrated both CCL2-tropic tumor trafficking and cytocidal reactivity against LK79 cells in vitro and in vivo. CCL2 augmented the WT1 epitope-responsive TCR signaling shown by relevant luciferase production in double gene-modified Jurkat/MA cells to express luciferase and WT1-specific TCR, and CCL2 also dose-dependently augmented WT1 epitope-responsive IFN-γ production and CD107a expression mediated by these double gene-modifiedCD3+ T cells.
Conclusion/Significance
Introduction of the CCL2/CCR2 axis successfully potentiated in vivo anti-lung cancer reactivity mediated by CD8+ T cells double gene-modified to express WT1-specific TCR and CCR2 not only via CCL2-tropic tumor trafficking, but also CCL2-enhanced WT1-responsiveness.
doi:10.1371/journal.pone.0056820
PMCID: PMC3575507  PMID: 23441216
4.  Novel CCL21-Vault Nanocapsule Intratumoral Delivery Inhibits Lung Cancer Growth 
PLoS ONE  2011;6(5):e18758.
Background
Based on our preclinical findings, we are assessing the efficacy of intratumoral injection of dendritic cells (DC) transduced with an adenoviral vector expressing the secondary lymphoid chemokine (CCL21) gene (Ad-CCL21-DC) in a phase I trial in advanced non-small cell lung cancer (NSCLC). While this approach shows immune enhancement, the preparation of autologous DC for CCL21 genetic modification is cumbersome, expensive and time consuming. We are evaluating a non-DC based approach which utilizes vault nanoparticles for intratumoral CCL21 delivery to mediate antitumor activity in lung cancer.
Principal Findings
Here we describe that vault nanocapsule platform for CCL21 delivery elicits antitumor activity with inhibition of lung cancer growth. Vault nanocapsule packaged CCL21 (CCL21-vaults) demonstrated functional activity in chemotactic and antigen presenting activity assays. Recombinant vaults impacted chemotactic migration of T cells and this effect was predominantly CCL21 dependent as CCL21 neutralization abrogated the CCL21 mediated enhancement in chemotaxis. Intratumoral administration of CCL21-vaults in mice bearing lung cancer enhanced leukocytic infiltrates (CXCR3+T, CCR7+T, IFNγ+T lymphocytes, DEC205+ DC), inhibited lung cancer tumor growth and reduced the frequencies of immune suppressive cells [myeloid derived suppressor cells (MDSC), T regulatory cells (Treg), IL-10 T cells]. CCL21-vaults induced systemic antitumor responses by augmenting splenic T cell lytic activity against parental tumor cells.
Significance
This study demonstrates that the vault nanocapsule can efficiently deliver CCL21 to sustain antitumor activity and inhibit lung cancer growth. The vault nanocapsule can serve as an “off the shelf” approach to deliver antitumor cytokines to treat a broad range of malignancies.
doi:10.1371/journal.pone.0018758
PMCID: PMC3086906  PMID: 21559281
5.  Cross talk between follicular helper T cells and tumor cells in human follicular lymphoma promotes immune evasion in the tumor microenvironment 
The microenvironment of human follicular lymphoma (FL), an incurable B-cell non-Hodgkin lymphoma, is thought to play a major role in its pathogenesis and course. Microenvironmental cells of likely importance include follicular helper T cells (TFH) and regulatory T cells (Tregs), and understanding their interactions with FL tumor cells is necessary to develop novel therapeutic strategies. We found that IL-4 and CD40L are expressed by intratumoral TFH and induce production of CCL17 and CCL22 by FL tumor cells. IL-4 alone induces only CCL17, but enhances stimulation by CD40L of both CCL17 and CCL22. Consistent with our in vitro results, mRNA transcripts of IL-4 correlated with CCL17 but not CCL22 in gene expression profiling studies of FL biopsies, whereas CD40L correlated with both CCL17 and CCL22. Tumor supernatants induced preferential migration of Tregs and IL-4–producing T cells rather than IFN-γ–producing T cells, and antibodies to CCR4 significantly abrogated the migration of Tregs. Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4–producing T cells, which in turn may stimulate more chemokine production in a feed-forward cycle. Thus, TFH appear to play a major role in generating an immunosuppressive tumor microenvironment that promotes immune escape and tumor survival and growth. Our results provide novel insights into the cross talk between TFH, tumor cells, and Tregs in FL and offer potential targets for development of therapeutic strategies to overcome immune evasion.
doi:10.4049/jimmunol.1201363
PMCID: PMC3680117  PMID: 23686488
6.  Systemic Blockade of Transforming Growth Factor-β (TGF-β) Signaling Augments the Efficacy of Immunogene Therapy 
Cancer research  2008;68(24):10247-10256.
Locally-produced TGF-β promotes tumor-induced immunosuppression and contributes to resistance to immunotherapy. This paper explores the potential for increased efficacy when combining immunotherapies with TGF-β suppression using the TGF-β type I receptor kinase inhibitor, SM16. Adenovirus expressing IFNβ (Ad.IFNβ) was injected intratumorally once in established subcutaneous AB12 (mesothelioma) and LKR (lung cancer) tumors or intratracheally in a K-ras orthotopic lung tumor model. Mice bearing TC1 (lung cancer) tumors were vaccinated with two injections of adenovirus expressing HPV-E7 (Ad.E7). SM16 was administered orally in formulated chow. Tumor growth was assessed and cytokine-expression and cell populations were measured in tumors and spleens by real time-PCR and flow cytometry. SM16 potentiated the efficacy of both immunotherapies in each of the models and caused changes in the tumor microenvironment. The combination of SM16 and Ad.INFβ increased the number of intratumoral leukocytes (including macrophages, NK cells, and CD8+ cells) and increased the percentage of T-cells expressing the activation marker CD25. SM16 also augmented the anti-tumor effects of Ad.E7 in the TC1 flank tumor model. The combination did not increase HPV-E7 tetramer-positive CD8+ T cells in the spleens, but did induce a marked increase in the tumors. Tumors from SM16-treated mice showed increased mRNA and protein for immunostimulatory cytokines and chemokines, as well as endothelial adhesion molecules, suggesting a mechanism for the increased intratumoral leukocyte trafficking. Blockade of the TGF-β signaling pathway augments the anti-tumor effects of Ad.INFβ immune-activating or Ad.E7 vaccination therapy. The addition of TGF-β blocking agents in clinical trials of immunotherapies may increase efficacy.
doi:10.1158/0008-5472.CAN-08-1494
PMCID: PMC2637471  PMID: 19074893
tumor immunology; immunosuppression; TGFβ; tumor associated macrophages; cytokines; lung cancer; mesothelioma; tumor vaccine; interferon-β
7.  CCL3 and CCL20-recruited dendritic cells modified by melanoma antigen gene-1 induce anti-tumor immunity against gastric cancer ex vivo and in vivo 
Background
To investigate whether dendritic cell (DC) precursors, recruited by injection of chemokine ligand 3 (CCL3) and CCL20, induce anti-tumor immunity against gastric cancer induced by a DC vaccine expressing melanoma antigen gene-1 (MAGE-1) ex vivo and in vivo.
Methods
B6 mice were injected with CCL3 and CCL20 via the tail vein. Freshly isolated F4/80-B220-CD11c+ cells cultured with cytokines were analyzed by phenotype analysis and mixed lymphocyte reaction (MLR). For adenoviral (Ad)-mediated gene transduction, cultured F4/80-B220-CD11c+ cells were incubated with Ad-MAGE-1. Vaccination of stimulated DC induced T lymphocytes. The killing effect of these T cells against gastric carcinoma cells was assayed by MTT. INF-γ production was determined with an INF-γ ELISA kit. In the solid tumor and metastases model, DC-based vaccines were used for immunization after challenge with MFC cells. Tumor size, survival of mice, and number of pulmonary metastatic foci were used to assess the therapeutic effect of DC vaccines.
Results
F4/80-B220-CD11c+ cell numbers increased after CCL3 and CCL20 injection. Freshly isolated F4/80-B220-CD11c+ cells cultured with cytokines were phenotyically identical to typical DC and gained the capacity to stimulate allogeneic T cells. These DCs were transduced with Ad-MAGE-1, which were prepared for DC vaccines expressing tumor antigen. T lymphocytes stimulated by DCs transduced with Ad-MAGE-1 exhibited specific killing effects on gastric carcinoma cells and produced high levels of INF-γ ex vivo. In vivo, tumor sizes of the experimental group were much smaller than both the positive control group and the negative control groups (P < 0.05). Kaplan-Meier survival curves showed that survival of the experimental group mice was significantly longer than the control groups (P < 0.05). In addition, MAGE-1-transduced DCs were also a therapeutic benefit on an established metastatic tumor, resulting in a tremendous decrease in the number of pulmonary metastatic foci.
Conclusions
CCL3 and CCL20-recruited DCs modified by adenovirus-trasnsduced, tumor-associated antigen, MAGE-1, can stimulate anti-tumor immunity specific to gastric cancer ex vivo and in vivo. This system may prove to be an efficient strategy for anti-tumor immunotherapy.
doi:10.1186/1756-9966-29-37
PMCID: PMC2873423  PMID: 20420712
8.  Depletion of CD4+ CD25+ Regulatory T Cells Promotes CCL21-Mediated Antitumor Immunity 
PLoS ONE  2013;8(9):e73952.
CCL21 is known to attract dendritic cells (DCs) and T cells that may reverse tumor-mediated immune suppression. The massive infiltration of tumors by regulatory T cells (Tregs) prevents the development of a successful helper immune response. In this study, we investigated whether elimination of CD4+ CD25+ Tregs in the tumor microenvironment using anti-CD25 monoclonal antibodies (mAbs) was capable of enhancing CCL21-mediated antitumor immunity in a mouse hepatocellular carcinoma (HCC) model. We found that CCL21 in combination with anti-CD25 mAbs (PC61) resulted in improved antitumor efficacy and prolonged survival, not only inhibited tumor angiogenesis and cell proliferation, but also led to significant increases in the frequency of CD4+, CD8+ T cells and CD11c+ DCs within the tumor, coincident with marked induction of tumor-specific CD8+ cytotoxic T lymphocytes (CTLs) at the local tumor site. The intratumoral immune responses were accompanied by the enhanced elaboration of IL-12 and IFN-γ, but reduced release of the immunosuppressive mediators IL-10 and TGF-β1. The results indicated that depletion of Tregs in the tumor microenvironment could enhance CCL21-mediated antitumor immunity, and CCL21 combined with anti-CD25 mAbs may be a more effective immunotherapy to promote tumor rejection.
doi:10.1371/journal.pone.0073952
PMCID: PMC3759453  PMID: 24023916
9.  Role of CCL11/eotaxin-1 signaling in ovarian cancer 
Purpose
Tumor cell growth and migration can be directly regulated by chemokines. In the present study the association of CCL11 with ovarian cancer has been investigated.
Experimental design and results
Circulating levels of CCL11 in sera of patients with ovarian cancer were significantly lower than those in healthy women or women with breast, lung, liver, pancreatic or colon cancers. Cultured ovarian carcinoma cells absorbed soluble CCL11 indicating that absorption by tumor cells could be responsible for the observed reduction of serum level of CCL11 in ovarian cancer. Postoperative CCL11 levels in women with ovarian cancer negatively correlated with relapse-free survival. Ovarian tumors overexpressed three known cognate receptors of CCL11, CCR2, CCR3, and CCR5. Strong positive correlation was observed between expression of individual receptors and tumor grade. CCL11 potently stimulated proliferation and migration/invasion of ovarian carcinoma cell lines, and these effects were inhibited by neutralizing antibodies against CCR2,3, and 5. The growth stimulatory effects of CCL11 were likely associated with activation of ERK1/2, MEK-1, and STAT3 phosphoproteins and with increased production of multiple cytokines, growth and angiogenic factors. Inhibition of CCL11 signaling by the combination of neutralizing antibodies against the ligand and its receptors significantly increased sensitivity to cisplatin in ovarian carcinoma cells. We conclude that CCL11 signaling plays an important role in proliferation and invasion of ovarian carcinoma cells and CCL11 pathway could be targeted for therapy in ovarian cancer. Furthermore, CCL11 could be used as a biomarker and a prognostic factor of relapse-free survival in ovarian cancer.
doi:10.1158/1078-0432.CCR-08-2024
PMCID: PMC2669845  PMID: 19351767
10.  Expression of a Functional CCR2 Receptor Enhances Tumor Localization and Tumor Eradication by Retargeted Human T Cells Expressing a Mesothelin - Specific Chimeric Antibody Receptor 
Purpose
Adoptive T cell immunotherapy (ACT) with tumor infiltrating lymphocytes or genetically-modified T cells has yielded dramatic results in some cancers. However, T cells need to traffic properly into tumors in order to adequately exert therapeutic effects.
Experimental Design
The chemokine CCL2 was highly secreted by malignant pleural mesotheliomas (MPM) (a planned tumor target), but the corresponding chemokine receptor (CCR2) was minimally expressed on activated human T cells transduced with a chimeric antibody receptor (CAR) directed to the MPM tumor antigen mesothelin (mesoCAR T cells). The chemokine receptor CCR2b was thus transduced into mesoCAR T cells using a lentiviral vector and the modified T cells were used to treat established mesothelin-expressing tumors.
Results
CCR2b transduction led to CCL2-induced calcium flux and increased transmigration, as well as augmentation of in vitro T cell killing ability. A single intravenous injection of 20 million mesoCAR + CCR2b T cells into immunodeficient mice bearing large, established tumors (without any adjunct therapy) resulted in a 12.5-fold increase in T cell tumor infiltration by Day 5 compared to mesoCAR T cells. This was associated with significantly increased anti-tumor activity.
Conclusions
CAR T cells bearing a functional chemokine receptor can overcome the inadequate tumor localization that limits conventional CAR targeting strategies and can significantly improve anti-tumor efficacy in vivo.
doi:10.1158/1078-0432.CCR-11-0351
PMCID: PMC3612507  PMID: 21610146
11.  Systemic Delivery of Neutralizing Antibody Targeting CCL2 for Glioma Therapy 
Journal of neuro-oncology  2010;104(1):83-92.
Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) inhibit anti-tumor immune responses and facilitate tumor growth. Precursors for these immune cell populations migrate to the tumor site in response to tumor secretion of chemokines, such as monocyte chemoattractant protein-1 (MCP-1/CCL2), which was originally purified and identified from human gliomas. In syngeneic mouse GL261 glioma and human U87 glioma xenograft models, we evaluated the efficacy of systemic CCL2 blockade by monoclonal antibodies (mAb) targeting mouse and/or human CCL2. Intraperitoneal (i.p.) administration of anti-mouse CCL2 mAb as monotherapy (2 mg/kg/dose, twice a week) significantly, albeit modestly, prolonged the survival of C57BL/6 mice bearing intracranial GL261 glioma (p=0.0033), which was concomitant with a decrease in TAMs and MDSCs in the tumor microenvironment. Similarly, survival was modestly prolonged in severe combined immunodeficiency (SCID) mice bearing intracranial human U87 glioma xenografts treated with both anti-human CCL2 mAb and anti-mouse CCL2 antibodies (2 mg/kg/dose for each, twice a week) compared to mice treated with control IgG (p=0.0159). Furthermore, i.p. administration of anti-mouse CCL2 antibody in combination with temozolomide (TMZ) significantly prolonged the survival of C57BL/6 mice bearing GL261 glioma with 8 of 10 treated mice surviving longer than 70 days, while only 3 of 10 mice treated with TMZ and isotype IgG survived longer than 70 days (p=0.0359). These observations provide support for development of mAb-based CCL2 blockade strategies in combination with the current standard TMZ-based chemotherapy for treatment of malignant gliomas.
doi:10.1007/s11060-010-0473-5
PMCID: PMC3068234  PMID: 21116835
glioma; chemokine; CCL2; monoclonal antibody; chemotherapy; temozolomide
12.  Clinical Implications of Co-Inhibitory Molecule Expression in the Tumor Microenvironment for DC Vaccination: A Game of Stop and Go 
The aim of therapeutic dendritic cell (DC) vaccines in cancer immunotherapy is to activate cytotoxic T cells to recognize and attack the tumor. T cell activation requires the interaction of the T cell receptor with a cognate major-histocompatibility complex-peptide complex. Although initiated by antigen engagement, it is the complex balance between co-stimulatory and co-inhibitory signals on DCs that results in T cell activation or tolerance. Even when already activated, tumor-specific T cells can be neutralized by the expression of co-inhibitory molecules on tumor cells. These and other immunosuppressive cues in the tumor microenvironment are major factors currently hampering the application of DC vaccination. In this review, we discuss recent data regarding the essential and complex role of co-inhibitory molecules in regulating the immune response within the tumor microenvironment. In particular, possible therapeutic intervention strategies aimed at reversing or neutralizing suppressive networks within the tumor microenvironment will be emphasized. Importantly, blocking co-inhibitory molecule signaling, often referred to as immune checkpoint blockade, does not necessarily lead to an effective activation of tumor-specific T cells. Therefore, combination of checkpoint blockade with other immune potentiating therapeutic strategies, such as DC vaccination, might serve as a synergistic combination, capable of reversing effector T cells immunosuppression while at the same time increasing the efficacy of T cell-mediated immunotherapies. This will ultimately result in long-term anti-tumor immunity.
doi:10.3389/fimmu.2013.00417
PMCID: PMC3847559  PMID: 24348481
DC vaccination; tumor microenvironment; checkpoint blockade; tumor-specific T cells; cancer treatment
13.  HMGB1 Mediates Endogenous TLR2 Activation and Brain Tumor Regression 
PLoS Medicine  2009;6(1):e1000010.
Background
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor that carries a 5-y survival rate of 5%. Attempts at eliciting a clinically relevant anti-GBM immune response in brain tumor patients have met with limited success, which is due to brain immune privilege, tumor immune evasion, and a paucity of dendritic cells (DCs) within the central nervous system. Herein we uncovered a novel pathway for the activation of an effective anti-GBM immune response mediated by high-mobility-group box 1 (HMGB1), an alarmin protein released from dying tumor cells, which acts as an endogenous ligand for Toll-like receptor 2 (TLR2) signaling on bone marrow-derived GBM-infiltrating DCs.
Methods and Findings
Using a combined immunotherapy/conditional cytotoxic approach that utilizes adenoviral vectors (Ad) expressing Fms-like tyrosine kinase 3 ligand (Flt3L) and thymidine kinase (TK) delivered into the tumor mass, we demonstrated that CD4+ and CD8+ T cells were required for tumor regression and immunological memory. Increased numbers of bone marrow-derived, tumor-infiltrating myeloid DCs (mDCs) were observed in response to the therapy. Infiltration of mDCs into the GBM, clonal expansion of antitumor T cells, and induction of an effective anti-GBM immune response were TLR2 dependent. We then proceeded to identify the endogenous ligand responsible for TLR2 signaling on tumor-infiltrating mDCs. We demonstrated that HMGB1 was released from dying tumor cells, in response to Ad-TK (+ gancyclovir [GCV]) treatment. Increased levels of HMGB1 were also detected in the serum of tumor-bearing Ad-Flt3L/Ad-TK (+GCV)-treated mice. Specific activation of TLR2 signaling was induced by supernatants from Ad-TK (+GCV)-treated GBM cells; this activation was blocked by glycyrrhizin (a specific HMGB1 inhibitor) or with antibodies to HMGB1. HMGB1 was also released from melanoma, small cell lung carcinoma, and glioma cells treated with radiation or temozolomide. Administration of either glycyrrhizin or anti-HMGB1 immunoglobulins to tumor-bearing Ad-Flt3L and Ad-TK treated mice, abolished therapeutic efficacy, highlighting the critical role played by HMGB1-mediated TLR2 signaling to elicit tumor regression. Therapeutic efficacy of Ad-Flt3L and Ad-TK (+GCV) treatment was demonstrated in a second glioma model and in an intracranial melanoma model with concomitant increases in the levels of circulating HMGB1.
Conclusions
Our data provide evidence for the molecular and cellular mechanisms that support the rationale for the clinical implementation of antibrain cancer immunotherapies in combination with tumor killing approaches in order to elicit effective antitumor immune responses, and thus, will impact clinical neuro-oncology practice.
Maria Castro and colleagues use cell line and transgenic mouse approaches to study the mechanisms underlying the immune response to glioblastoma multiforme.
Editors' Summary
Background.
Every year, more than 175,000 people develop a primary brain tumor (a cancer that starts in the brain rather than spreading in from elsewhere). Like all cancers, brain tumors develop when a cell acquires genetic changes that allow it to grow uncontrollably and that change other aspects of its behavior, including the proteins it makes. There are many different types of cells in the brain and, as a result, there are many different types of brain tumors. However, one in five primary brain tumors is glioblastoma multiforme (GBM; also known as grade 4 astrocytoma), a particularly aggressive cancer. With GBM, the average time from diagnosis to death is one year and only one person in 20 survives for five years after a diagnosis of GBM. Symptoms of GBM include headaches, seizures, and changes in memory, mood, or mental capacity. Treatments for GBM, which include surgery, radiotherapy, and chemotherapy, do not “cure” the tumor but they can ease these symptoms.
Why Was This Study Done?
Better treatments for GBM are badly needed, and one avenue that is being explored is immunotherapy—a treatment in which the immune system is used to fight the cancer. Because many tumors make unusual proteins, the immune system can sometimes be encouraged to recognize tumor cells as foreign invaders and kill them. Unfortunately, attempts to induce a clinically useful anti-GBM immune response have been unsuccessful, partly because the brain contains very few dendritic cells, a type of immune system cell that kick-starts effective immune responses by presenting foreign proteins to other immune system cells. Another barrier to immunotherapy for GBM is immune evasion by the tumor. Many tumors develop ways to avoid the immune response as they grow. For example, they sometimes reduce the expression of proteins that the immune system might recognize as foreign. In this study, the researchers test a new combined treatment strategy for GBM in which dendritic cells are encouraged to enter the brain and tumor cells are killed to release proteins capable of stimulating an effective antitumor immune response.
What Did the Researchers Do and Find?
The researchers first established brain tumors in mice. Then, they injected harmless viruses carrying the genes for Fms-like tyrosine kinase 3 ligand (Ftl3L; a protein that attracts dendritic cells) and for thymidine kinase (TK; cells expressing TK are killed by a drug called gancyclovir) into the tumor. Expression of both Flt3L and TK (but not of either protein alone) plus gancyclovir treatment shrank the tumors and greatly improved the survival of the mice. The researchers show that their strategy increased the migration of dendritic cells into the tumor provided they expressed an immune system protein called Toll-like receptor 2 (TLR2). TLR2 expression on the dendritic cells was also needed for an effective anti-tumor immune response and for tumor regression. TLR2 normally activates dendritic cells by binding to specific proteins on invading pathogens, so what was TLR2 binding to in the mouse tumors? The researchers reveal that TLR2 was responding to high-mobility-group box 1 (HMGB1), a protein released by the dying tumor cells by showing that treatment of the tumor-bearing mice with the HMGB1 inhibitor glycyrrhizin blocked the therapeutic effect of Flt3L/TK expression. Finally, the researchers report that other tumor cell types release HMGB1 when they are killed and that the Flt3L/TK expression strategy can also kill other tumors growing in mouse brains.
What Do These Findings Mean?
Results obtained in mouse models of human diseases do not always lead to effective treatments for human patients. Nevertheless, the findings of this study provide new insights into how an effective immune response against brain tumors might be brought about. Most importantly, they show that an effective strategy might need to both attract dendritic cells into the brain tumor and to kill tumor cells, so they release proteins that can activate the dendritic cells. That is, the authors suggest it's important to combine immunotherapies with tumor-killing strategies to provide effective treatments for primary and metastatic brain tumors
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000010.
The US National Cancer Institute provides information about brain tumors for patients and health professionals and about the the immune system and how it can be harnessed to fight cancer (in English and Spanish)
Cancer Research UK provides information on all aspects of brain tumors for patients and their caregivers
MedlinePlus provides links to further information about brain cancer, (including some links to information in Spanish)
The American Brain Tumor Association provides brain tumor resources and information
The National Brain Tumor Society provides educational and support services regarding brain tumors
doi:10.1371/journal.pmed.1000010
PMCID: PMC2621261  PMID: 19143470
14.  Mechanisms Involved in Radiation Enhancement of Intratumoral Dendritic Cell Therapy 
We have previously reported that local tumor irradiation, without inducing cell death, can augment the therapeutic efficacy of intratumoral (i.t.) dendritic cell (DC) vaccination. This study examined potential mechanisms underlying radiation enhancement of i.t. DC therapy in this setting. Even though ionizing radiation did not mediate tumor cell kill, bone marrow-derived DCs acquired in vitro tumor antigens from irradiated D5 murine melanoma cells more efficiently than from untreated cells. This radiation-enhanced loading of DCs did not induce DC maturation, but was associated with improved cross-priming of T cells both in vitro and in vivo. Furthermore, in vivo pulsing of DCs with irradiated versus untreated tumor cells resulted in superior presentation of tumor antigens to T cells. In addition, tumor irradiation facilitated homing of i.t. administered DCs to the draining lymph node, possibly by down-regulating CCL21 expression within the tumor mass. Studies of the tumor microenvironment in irradiated versus untreated tumors did not reveal significant inflammatory changes. Moreover, radiation did not promote accumulation of CD4+ or CD8+ effector T cells within solid tumors. Our results indicate that, without inducing cytotoxicity, tumor irradiation can enhance the ability of DCs to capture tumor antigens, migrate to the draining lymph node, and present processed antigens to T cells. These findings may prove useful in designing future strategies for human cancer immunotherapy.
doi:10.1097/CJI.0b013e318163628c
PMCID: PMC3103774  PMID: 18391761
Cancer vaccines; Cellular immunotherapy; Dendritic cells; Radiation; Tumor immunology
15.  Natural Killer T Cells Infiltrate Neuroblastomas Expressing the Chemokine CCL2 
The Journal of Experimental Medicine  2004;199(9):1213-1221.
CD1d-restricted Vα24-Jα18–invariant natural killer T cells (iNKTs) are potentially important in tumor immunity. However, little is known about their localization to tumors. We analyzed 98 untreated primary neuroblastomas from patients with metastatic disease (stage 4) for tumor-infiltrating iNKTs using TaqMan® reverse transcription polymerase chain reaction and immunofluorescent microscopy. 52 tumors (53%) contained iNKTs, and oligonucleotide microarray analysis of the iNKT+ and iNKT− tumors revealed that the former expressed higher levels of CCL2/MCP-1, CXCL12/SDF-1, CCL5/RANTES, and CCL21/SLC. Eight tested neuroblastoma cell lines secreted a range of CCL2 (0–21.6 ng/ml), little CXCL12 (≤0.1 ng/ml), and no detectable CCL5 or CCL21. CCR2, the receptor for CCL2, was more frequently expressed by iNKT compared with natural killer and T cells from blood (P < 0.001). Supernatants of neuroblastoma cell lines that produced CCL2 induced in vitro migration of iNKTs from blood of patients and normal adults; this was abrogated by an anti-CCL2 monoclonal antibody. CCL2 expression by tumors was found to inversely correlate with MYCN proto-oncogene amplification and expression (r = 0.5, P < 0.001), and MYCN-high/CCL2-low expression accurately predicted the absence of iNKTs (P < 0.001). In summary, iNKTs migrate toward neuroblastoma cells in a CCL2-dependent manner, preferentially infiltrating MYCN nonamplified tumors that express CCL2.
doi:10.1084/jem.20031462
PMCID: PMC2211904  PMID: 15123743
lymphocytes; tumor-infiltrating; T lymphocyte subsets; cell movement; immunologic surveillance
16.  Inhibition of CCL2 Signaling in Combination with Docetaxel Treatment Has Profound Inhibitory Effects on Prostate Cancer Growth in Bone 
The C-C chemokine ligand 2 (CCL2) stimulates migration, proliferation, and invasion of prostate cancer (PCa) cells, and its signaling also plays a role in the activation of osteoclasts. Therefore targeting CCL2 signaling in regulation of tumor progression in bone metastases is an area of intense research. The objective of our study was to investigate the efficacy of CCL2 blockade by neutralizing antibodies to inhibit the growth of PCa in bone. We used a preclinical model of cancer growth in the bone in which PCa C4-2B cells were injected directly into murine tibiae. Animals were treated for ten weeks with neutralizing anti-CCL2 antibodies, docetaxel, or a combination of both, and then followed an additional nine weeks. CCL2 blockade inhibited the growth of PCa in bone, with even more pronounced inhibition in combination with docetaxel. CCL2 blockade also resulted in increases in bone mineral density. Furthermore, our results showed that the tumor inhibition lasted even after discontinuation of the treatment. Our data provide compelling evidence that CCL2 blockade slows PCa growth in bone, both alone and in combination with docetaxel. These results support the continued investigations of CCL2 blockade as a treatment for advanced metastatic PCa.
doi:10.3390/ijms140510483
PMCID: PMC3676850  PMID: 23698775
prostate cancer; bone metastases; chemokine; CCL2; docetaxel; bone metastases
17.  CCL5-MEDIATED ENDOGENOUS ANTI-TUMOR IMMUNITY ELICITED BY ADOPTIVELY TRANSFERRED LYMPHOCYTES AND DENDRITIC CELL DEPLETION 
Cancer research  2009;69(15):6331-6338.
Adoptive transfer of anti-tumor T cells is a promisingly effective therapy for various cancers, but its effect on endogenous anti-tumor immune mechanisms remains largely unknown. Here we demonstrate that the administration of naïve T cells de novo primed for only 7 days against tumor antigens resulted in the durable rejection of otherwise lethal ovarian cancers when coupled with the depletion of tumor-associated immunosuppressive dendritic cells (DCs). Therapeutic activity required tumor antigen specificity and perforin expression by the adoptively transferred T cells, but not IFN-γ production. Importantly, these shortly primed T cells secreted large amounts of CCL5, which was required for their therapeutic benefit. Accordingly, transferred T cells recruited CCR5+ DCs into the tumor, where they showed distinct immunostimulatory attributes. Activated CCR5+ host T cells with anti-tumor activity also accumulated at tumor locations, and endogenous tumor-specific memory T cells remained elevated after the disappearance of transferred lymphocytes. Therefore, persistent, long-lived anti-tumor immunity was triggered by the administration of ex vivo activated T cells, but was directly mediated by immune cells of host origin. Our data unveil a CCL5-dependent mechanism of awakening endogenous anti-tumor immunity triggered by ex vivo expanded T cells, which is augmented by tumor-specific targeting of the cancer microenvironment.
doi:10.1158/0008-5472.CAN-08-4329
PMCID: PMC2755640  PMID: 19602595
18.  Immunology and Immunotherapy of Neuroblastoma 
Seminars in cancer biology  2011;21(4):229-237.
Purpose
This review demonstrates the importance of immunobiology and immunotherapy research for understanding and treating neuroblastoma.
Principal results
The first suggestions of immune system-neuroblastoma interactions came from in vitro experiments showing that lymphocytes from patients were cytotoxic for their own tumor cells and from evaluations of tumors from patients that showed infiltrations of immune system cells. With the development of monoclonal antibody (mAb) technology, a number of mAbs were generated against neuroblastoma cells lines and were used to define tumor associated antigens. Disialoganglioside (GD2) is one such antigen that is highly expressed by virtually all neuroblastoma cells and so is a useful target for both identification and treatment of tumor cells with mAbs. Preclinical research using in vitro and transplantable tumor models of neuroblastoma has demonstrated that cytotoxic T lymphocytes (CTLs) can specifically recognize and kill tumor cells as a result of vaccination or of genetic engineering that endows them with chimeric antigen receptors. However, CTL based clinical trials have not progressed beyond pilot and phase I studies. In contrast, anti-GD2 mAbs have been extensively studied and modified in pre-clinical experiments and have progressed from phase I through phase III clinical trials. Thus, the one proven beneficial immunotherapy for patients with high-risk neuroblastoma uses a chimeric anti-GD2 mAb combined with IL-2 and GM-CSF to treat patients after they have received intensive cyto-reductive chemotherapy, irradiation, and surgery. Ongoing pre-clinical and clinical research emphasizes vaccine, adoptive cell therapy, and mAb strategies. Recently it was shown that the neuroblastoma microenvironment is immunosuppressive and tumor growth promoting, and strategies to overcome this are being developed to enhance anti-tumor immunotherapy.
Conclusions
Our understanding of the immunobiology of neuroblastoma has increased immensely over the past 40 years, and clinical translation has shown that mAb based immunotherapy can contribute to improving treatment for high-risk patients. Continued immunobiology and pre-clinical therapeutic research will be translated into even more effective immunotherapeutic strategies that will be integrated with new cytotoxic drug and irradiation therapies to improve survival and quality of life for patients with high-risk neuroblastoma.
doi:10.1016/j.semcancer.2011.09.012
PMCID: PMC3658311  PMID: 21971567
neuroblastoma; immunology; immunotherapy; microenvironment; anti-GD2
19.  TIMP-2 targets tumor associated-myeloid suppressor cells with effects in cancer immune dysfunction and angiogenesis 
Angiogenesis and inflammation are important therapeutic targets in non-small cell lung cancer (NSCLC). It is well known that proteolysis mediated by matrix metalloproteinases (MMPs) promotes angiogenesis and inflammation in the tumor microenvironment. Here, the effects of the MMP-inhibitor TIMP-2 on NSCLC inflammation and angiogenesis were evaluated in TIMP-2 deficient (timp2−/−) mice injected subcutaneously with Lewis-Lung carcinoma cells and compared with the effects on tumors in wild-type (WT) mice. TIMP-2-deficient mice demonstrated increased tumor growth, enhanced expression of angiogenic marker αv β3 in tumor and endothelial cells and significantly higher serum-VEGF-A levels. Tumor-bearing-timp2−/− mice showed a significant number of inflammatory cells in their tumors, upregulation of inflammation mediators, NF-κB and Annexin A1, as well as higher levels of serum IL-6. Phenotypic analysis revealed an increase in myeloid-derived-suppressor-cell (MDSC) cells (CD11b+, Gr-1+) that co-expressed VEGF-R1+ and elevated MMP activation present in tumors and spleens from timp2−/− mice. Furthermore, TIMP-2-deficient tumors up-regulated expression of the immunosuppressing genes controlling MDSC growth, IL-10, IL-13, IL-11, and CCL-5/RANTES, as well as decreased IFN-γ and increased CD40L. Moreover, forced TIMP-2 expression in human lung-adenocarcinoma A-549 resulted in a significant reduction of MDSCs recruited into tumors, as well as suppression of angiogenesis and tumor growth. The increase in MDSCs has been linked to cancer immunosuppression and angiogenesis. Therefore, this study supports TIMP-2 as a negative regulator of MDSCs with important implications for the immunotherapy and /or anti-angiogenic treatment of NSCLC.
doi:10.1097/CJI.0b013e3182619c8e
PMCID: PMC3402087  PMID: 22735808
20.  Beneficial Impact of CCL2 and CCL12 Neutralization on Experimental Malignant Pleural Effusion 
PLoS ONE  2013;8(8):e71207.
Using genetic interventions, we previously determined that C-C motif chemokine ligand 2 (CCL2) promotes malignant pleural effusion (MPE) formation in mice. Here we conducted preclinical studies aimed at assessing the specific therapeutic potential of antibody-mediated CCL2 blockade against MPE. For this, murine MPEs or skin tumors were generated in C57BL/6 mice by intrapleural or subcutaneous delivery of lung (LLC) or colon (MC38) adenocarcinoma cells. Human lung adenocarcinoma cells (A549) were used to induce MPEs in severe combined immunodeficient mice. Intraperitoneal antibodies neutralizing mouse CCL2 and/or CCL12, a murine CCL2 ortholog, were administered at 10 or 50 mg/kg every three days. We found that high doses of CCL2/12 neutralizing antibody treatment (50 mg/kg) were required to limit MPE formation by LLC cells. CCL2 and CCL12 blockade were equally potent inhibitors of MPE development by LLC cells. Combined CCL2 and CCL12 neutralization was also effective against MC38-induced MPE and prolonged the survival of mice in both syngeneic models. Mouse-specific CCL2-blockade limited A549-caused xenogeneic MPE, indicating that host-derived CCL2 also contributes to MPE precipitation in mice. The impact of CCL2/12 antagonism was associated with inhibition of immune and vascular MPE-related phenomena, such as inflammation, new blood vessel assembly and plasma extravasation into the pleural space. We conclude that CCL2 and CCL12 blockade are effective against experimental MPE induced by murine and human adenocarcinoma in mice. These results suggest that CCL2-targeted therapies may hold promise for future use against human MPE.
doi:10.1371/journal.pone.0071207
PMCID: PMC3743892  PMID: 23967166
21.  System-Wide Analysis Reveals a Complex Network of Tumor-Fibroblast Interactions Involved in Tumorigenicity 
PLoS Genetics  2013;9(9):e1003789.
Many fibroblast-secreted proteins promote tumorigenicity, and several factors secreted by cancer cells have in turn been proposed to induce these proteins. It is not clear whether there are single dominant pathways underlying these interactions or whether they involve multiple pathways acting in parallel. Here, we identified 42 fibroblast-secreted factors induced by breast cancer cells using comparative genomic analysis. To determine what fraction was active in promoting tumorigenicity, we chose five representative fibroblast-secreted factors for in vivo analysis. We found that the majority (three out of five) played equally major roles in promoting tumorigenicity, and intriguingly, each one had distinct effects on the tumor microenvironment. Specifically, fibroblast-secreted amphiregulin promoted breast cancer cell survival, whereas the chemokine CCL7 stimulated tumor cell proliferation while CCL2 promoted innate immune cell infiltration and angiogenesis. The other two factors tested had minor (CCL8) or minimally (STC1) significant effects on the ability of fibroblasts to promote tumor growth. The importance of parallel interactions between fibroblasts and cancer cells was tested by simultaneously targeting fibroblast-secreted amphiregulin and the CCL7 receptor on cancer cells, and this was significantly more efficacious than blocking either pathway alone. We further explored the concept of parallel interactions by testing the extent to which induction of critical fibroblast-secreted proteins could be achieved by single, previously identified, factors produced by breast cancer cells. We found that although single factors could induce a subset of genes, even combinations of factors failed to induce the full repertoire of functionally important fibroblast-secreted proteins. Together, these results delineate a complex network of tumor-fibroblast interactions that act in parallel to promote tumorigenicity and suggest that effective anti-stromal therapeutic strategies will need to be multi-targeted.
Author Summary
There is increasing interest in developing methods to treat cancer by targeting non-cancer cells that play supportive roles in the tumor microenvironment. One type of non-cancer cell that has received considerable attention along these lines is cancer-associated fibroblasts, which can promote tumor formation and tumor growth. There have been several studies showing that inhibition of individual fibroblast genes or proteins dramatically reduces the tumor supportive function of fibroblasts. From the perspective of developing a therapeutic strategy, what remains unclear is whether the several different important factors discovered to date reflect the requirement of a multitude of fibroblast factors to promote tumorigenicity, or whether it reflects the diversity of the epithelial cancer cells and fibroblasts used in these different studies. Here, we addressed this question directly using a single system of fibroblasts and breast cancer epithelial cells. Importantly, we found that a multitude of fibroblast factors are indeed required to promote tumorigenicity, and that they have different effects on the tumor microenvironment. Furthermore, we found that inhibiting multiple fibroblast-secreted factors is more efficacious than blocking individual factors. These results suggest that fibroblasts and cancer cells act through multiple parallel pathways and that effective anti-stromal therapeutic strategies will need to be multi-targeted.
doi:10.1371/journal.pgen.1003789
PMCID: PMC3778011  PMID: 24068959
22.  Regulated Expression of CCL21 in the Prostate Tumor Microenvironment Inhibits Tumor Growth and Metastasis in an Orthotopic Model of Prostate Cancer 
Cancer Microenvironment  2009;2(1):59-67.
Currently there are no curative therapies available for patients with metastatic prostate cancer. Thus, novel therapies are needed to treat this patient population. Immunotherapy represents one promising approach for the elimination of occult metastatic tumors. However, the prostate tumor microenvironment (TME) represents a hostile environment capable of suppressing anti-tumor immunity and effector cell function. In view of this immunosuppressive activity, we engineered murine prostate cancer cells with regulated expression (tet-on) of CCL21. Prostate tumor cells implanted orthotopically produced primary prostate tumors with predictable metastatic disease in draining lymph nodes and distant organs. Expression of CCL21 in the prostate TME enhanced survival, inhibited tumor growth and decreased the frequency of local (draining lymph node) and distant metastasis. Therefore, these studies provide a strong rationale for further evaluation of CCL21 in tumor immunity and its use in cancer immunotherapy.
doi:10.1007/s12307-009-0021-z
PMCID: PMC2787929  PMID: 19418243
Tumor microenvironment; CCL21; Prostate cancer; TRAMP; T-REx system; Cancer immunosupression
23.  Regulated Expression of CCL21 in the Prostate Tumor Microenvironment Inhibits Tumor Growth and Metastasis in an Orthotopic Model of Prostate Cancer 
Cancer Microenvironment  2009;2(1):59-67.
Currently there are no curative therapies available for patients with metastatic prostate cancer. Thus, novel therapies are needed to treat this patient population. Immunotherapy represents one promising approach for the elimination of occult metastatic tumors. However, the prostate tumor microenvironment (TME) represents a hostile environment capable of suppressing anti-tumor immunity and effector cell function. In view of this immunosuppressive activity, we engineered murine prostate cancer cells with regulated expression (tet-on) of CCL21. Prostate tumor cells implanted orthotopically produced primary prostate tumors with predictable metastatic disease in draining lymph nodes and distant organs. Expression of CCL21 in the prostate TME enhanced survival, inhibited tumor growth and decreased the frequency of local (draining lymph node) and distant metastasis. Therefore, these studies provide a strong rationale for further evaluation of CCL21 in tumor immunity and its use in cancer immunotherapy.
doi:10.1007/s12307-009-0021-z
PMCID: PMC2787929  PMID: 19418243
Tumor microenvironment; CCL21; Prostate cancer; TRAMP; T-REx system; Cancer immunosupression
24.  Chemotherapeutic drugs and human tumor cells cytokine network 
The ability of human tumor cell lines to produce various cytokines, chemokines, angiogenic and growth factors was investigated using Luminex multiplex technology. Media conditioned by tumor cells protected tumor cells from drug-induced apoptosis and stimulated tumor cell proliferation. Antibodies neutralizing IL-6, CXCL8, CCL2 and CCL5 blocked this stimulation. Treatment of tumor cells with doxorubicin and cisplatin resulted in a substantial increase in the production of IL-6, CXCL8, CCL2, CCL5, BFGF, G-CSF, and VEGF. This stimulation was associated with drug-induced activation of NF-κB, AP-1, AP-2, CREB, HIF-1, STAT-1, STAT-3, STAT-5 and ATF-2 transcription factors and up-regulation of IL-6, CXCL8, FGF-2, CSF-3 and CCL5 gene expression. Treatment of tumor cells with doxorubicin and antibodies neutralizing G-CSF, CCL2 or CCL5 had higher inhibitory effects than each modality used alone. These results indicate that chemokines and growth factors produced by tumor by binding to the cognate receptors on tumor and stroma cells could provide proliferative and anti-apoptotic signals helping tumor to escape drug-mediated destruction. Clinical studies showed that antibodies neutralizing VEGF (Avastin/ Bevacizumab) or blocking HER2/neu signaling (Herceptin/ Trastuzumab) could increase the efficacy of chemotherapy although these beneficial effects have been limited. It is possible that drug-stimulated production of growth and pro-angiogenic factors could counterbalance the effects of antibody therapy. In addition, numerous growth factors and chemokines share angiogenic and growth-stimulating properties, and thus reduction of a single factor is insufficient to completely block tumor growth. Thus, a broad disruption of tumor cytokine network is needed to further increase the efficacy of cancer therapy.
doi:10.1002/ijc.23732
PMCID: PMC2574811  PMID: 18697197
tumor cells; drugs; cytokines; chemokines; angiogenic factors
25.  Radiotherapy Augments the Immune Response to Prostate Cancer in a Time-Dependent Manner 
The Prostate  2008;68(12):1319-1329.
Background
Cancer immunotherapy refers to an array of strategies intended to treat progressive tumors by augmenting a patient’s anti-tumor immune response. As immunotherapy is eventually incorporated into oncology treatment paradigms, it is important to understand how these therapies interact with established cancer treatments such as chemotherapy or Radiotherapy (RT). To address this, we utilized a well-established, autochthonous murine model of prostate cancer to test whether RT could augment (or diminish) the CD4 T cell response to a tumor vaccine.
Methods
Transgenic mice that develop spontaneous prostate cancer (TRAMP) which also express a unique tumor associated antigen (Influenza hemagglutinin) under the control of a prostate-specific promoter were given local RT in combination with immunotherapy. The immunological outcome of this combinatorial strategy was assayed by monitoring the effector response of adoptively transferred, prostate-specific CD4 T cells.
Results
Neither RT nor immunotherapy alone was capable of priming an anti-tumor immune response in animals with evolving tumors. The combination of immunotherapy with RT resulted in anti-tumor T cell activation – this effect was profoundly dependent on the relative timing of RT and immunotherapy. Anti-tumor immune responses occurred when immunotherapy was administered 3-5 weeks post-RT, but such responses were undetectable when immunotherapy was administered either earlier (peri-radiothrerapy) or later.
Conclusions
The therapeutic temporal window of immunotherapy post-RT suggests that highly aggressive, immuno-suppressive tumors might be most sensitive to immunotherapy in a fairly narrow time window; these results should help to guide future development of clinical combinatorial strategies.
doi:10.1002/pros.20794
PMCID: PMC2710770  PMID: 18561247
Radiation; Immunotherapy; TRAMP; T Cell; vaccine

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