Dr. Tak Mak explored the role of the immune system in oncogenesis, focusing on the NFκB family of transcription factors, which play a key role in coordinating immune response. Inflammatory cells typically respond to bacteria, viruses, necrotic cell products and various cytokines by activating NFκB. Although a mediator of normal immune response, NFκB's aberrant consequences have been shown in many malignancies to influence growth, angiogenesis, apoptosis, and evolution to an invasive phenotype. Dr. Mak reviewed NFκB activation in Hodgkin's and MALT lymphomas, citing paradoxical effects with regard to apoptosis, such as a recently reported therapeutic window related to the expected TNFα activation of a pro-survival NFκB pathway favoring tumor progression. In the absence of cIAP1 and cIAP2 (cellular inhibitor of apoptosis 1 and 2 proteins), TNFα defaults to the pro-death extrinsic apoptosis pathway. Other opportunities to modulate NFκB's chemopreventive potential are apparent, but require examination for any tissue-specific toxicities.
Attention to mediators of inflammation and immunity was next directed toward tumor-associated macrophages (TAM), which have the potential to mediate either pro- or anti-tumor activity. Dr. Michael Pollard focused on the appropriation of macrophage function by tumor cells through tumor-stromal interactions. The classic symbiotic interaction between tumor cells and TAMs has been described as one in which tumor cells recruit TAMs to the tumor mass. TAMs in turn adapt to the hypoxic tumor microenvironment by producing mutually beneficial mitogens and growth factors. Hence, a high density of tumor macrophages may portend a poor prognosis. This concept is experimentally supported by a mouse model that demonstrates that tumor progression is delayed by the deletion of macrophage colony stimulating factor-1 (CSF-1, a primary TAM regulator), which deprives the system of TAM-mediated activation of the angiogenic switch.
Tumor-associated myeloid-derived suppressor cells (MDSC) are another group of immune effector cells that are attracted into the tumor microenvironment. MDSC are recruited and retained by tumors, where they block T cell activation and the production of natural killer cells, and also promote T cell tolerance of tumor. Dr. Suzanne Ostrand-Rosenberg explored the interplay between inflammation and tumor-induced immune suppression in her discussion of crosstalk between murine MDSC and macrophages. In response to macrophages, MDSC increase their production of IL-10 and cause a decrease in IL-12 production in the macrophage population, leading to a relative expansion of the alternatively activated, pro-tumor macrophage phenotype (M2) as compared to the classically activated, anti-tumor phenotype (M1). The S100 family of inflammatory mediators (including prostaglandin E2 and IL-1β) sustains MDSC accumulation via NFκB- related pathways, suggesting promising avenues for cancer immunoprevention.
Opportunities to suppress tumor growth by targeting MDSC were discussed by Dr. Augusto Ochoa. Many human solid tumors (e.g., renal, colon, head and neck, and lung cancers) escape anti-tumor surveillance and induce tumor tolerance via immunomodulation. This is achieved by “hijacking” the normal tissue remodeling response, as demonstrated by MDSC activity in the tumor microenvironment. Arginine depletion is a key mechanism influencing T cell function, a classic characteristic of immune anergy that ultimately enhances tumor growth. In human renal cell carcinoma, a tumor-expanded population of MDSC releases arginase I into the circulation, depletes T cells of L-arginine, and thereby contributes to a profound derangement of T cell function. In preclinical systems, arginase inhibition with nor-NOHA (Nω-hydroxy-nor-L-arginine), sildenafil, and a COX-2 inhibitor (sc-58125) have been shown to reverse MDSC-mediated arginase I immune suppression, suggesting the clinical utility of immunotherapies that reduce MDSC and decrease plasma levels of arginase I.
Oncogene-induced cellular senescence (OIS) is an anti-proliferative response that limits the proliferation of early neoplastic cells. OIS occurs in advance of replicative senescence that is related to telomere-shortening. Dr. Daniel Peeper discussed interleukin-6 (IL-6), which acts as a central regulator of an inflammatory network that induces OIS and can stimulate the proliferation of cells that have lost the ability to senesce. As a result, OIS is gaining attention as a possible explanation for growth arrest in proliferative lesions that do not undergo malignant transformation, such as melanocytic nevi. There is great interest in understanding mechanisms underlying this process, which might be exploited to reduce cancer risk.
Dr. Andrew Chan presented data supporting a role for chronic inflammation in the pathogenesis of sporadic colorectal cancer (CRC). He explored whether routine aspirin use preferentially reduced the risk of cyclooxygenase-2 (COX-2) positive tumors and showed that certain subsets of the population may derive different levels of benefit from anti-inflammatory drugs. Aspirin has been shown to decrease cellular proliferation and increase apoptosis by a variety of mechanisms, including the inhibition of cyclooxygenase-2 (COX-2), inhibition of nuclear factor-KB, induction of p38 kinase and polyamine catabolism. Dr. Chan's pooled analysis of the Nurses Health Study (N=121,700) and the Health Professionals Follow-up Study (N=51,539) found a statistically significant 36% reduced risk of COX-2 positive CRC among regular aspirin users (at least 2 tablets weekly), as compared to non-aspirin users. This analysis also detected a significant trend toward further decreases in COX-2 positive CRC risk with increased aspirin dose and duration of use. Data showing associations between higher pre-diagnostic levels of soluble tumor necrosis factor receptor 2 (sTNF-R2), an inflammatory marker, and the likelihood of benefit from anti-inflammatory drugs to reduce the risk of CRC were also shown.