Several groups, including our own[23
], have suggested that prostate cancer may arise in a setting of chronic inflammation, with early pre-malignant lesions detectable adjacent to areas marked by an inflammatory infiltrate[24
]. This observation suggests that prostate cancer may be recognized by the adaptive immune system, a finding supported by the detection of prostate-associated antibodies in the sera of prostate cancer patients in multiple studies[25
]. Several of these studies focused on the use of serum antibody levels (or serum antibody profile) as a potential tool for prostate cancer diagnosis[25
], while other groups suggested that antibody induction may be associated with treatment. In that regard, antigen-specific antibody responses have been noted in patients treated with either hormonal or radiation therapy[28
]. Interestingly, one group has described antibodies to the ligand-binding domain of the androgen-receptor. As this region is normally intracellular, these data suggest that antibody induction could be driven by processes associated with tissue destruction and immunogenic recognition of associated proteins[29
]. In the present study, we show that treatment of men with biochemically recurrent prostate cancer with lenalidomide resulted in the induction of new prostate–associated antibodies. This induction was greater than that observed in men treated with ADT alone. These data are novel in that we were unable to find prior reports showing the induction (or augmentation) of cancer tissue-related antibodies in response to lenalidomide treatment in the current literature. Moreover, these results are consistent with recent data showing that patients with multiple myeloma mounted an augmented response to a polyvalent pneumococcal vaccine if under treatment with lenalidomide at the time of vaccination (Borrello, I, unpublished). It is thus tempting to speculate that these data suggest that a novel mechanism of action for lenalidomide might be the induction of anti-tumor antibodies, but this hypothesis requires further evaluation in prospective clinical trials.
The proximal mechanism for the augmented antibody responses we noted here appears to be related to the cytokine changes we observed in patients after lenalidomide treatment. As previously reported, we found augmented IL-2 levels in treated patients[8
]. This effect may be mediated by increased PKC-θ activation in T cells[30
] as well as by increased AP-1 transcriptional activity[31
]. We also noted a relative increase in the cytokines IL-4, IL-5, IL-10 and IL-13 in patients treated with lenalidomide. This represents a canonical TH
2 cytokine profile[32
], classically associated with a humoral immune response and antibody production[33
]. This finding is perhaps not entirely consistent with previous work on the effects of lenalidomide-related agents on human T cells; in one of these studies a relative TH
1 skewing was noted[34
]. However, the relative TH
1 versus TH
2 skewing properties of the imide family of drugs is not completely clear; in another study, augmentation of cytokine production from both TH
1 and TH
2 cells was noted[31
]. From that perspective, our data are thus consistent with the notion that lenalidomide treatment of patients with biochemically recurrent prostate cancer may boost an existing TH
2 skewed response, rather than induce a response from naïve CD4 T cells or reprogram a pre-existing TH
]. Regardless of the precise mechanism involved, the induction of new anti-prostate antibodies after lenalidomide treatment is certainly consistent with the cytokine profile we observe here.
Perhaps the most interesting aspect of our data is the observation of a dichotomous trend in IL-8 levels in patients classified as lenalidomide “responders” versus “non-responders”: with IL-8 levels decreasing in patients who appeared to derive potential benefit from treatment, and increasing in patients with “progressive” disease. IL-8 is a pleotropic cytokine, produced by several cell types and affecting multiple cellular processes. Immunologically, IL-8 has a well-documented role in neutrophil recruitment[36
]. In that light, it is interesting to note recent data showing that the corpora amylacea in men with prostate cancer contain lactoferrin and several other neutrophil-derived proteins, suggesting a potential role for neutrophil-mediated inflammation in prostate carcinogenesis[37
]. In addition to a potential role in inflammation-associated tumor promotion, a second mechanism by which IL-8 might promote tumor progression involves angiogenesis. Expression of the receptors for IL-8 (CXR-1 and CXR-2) has been documented on tumor-associated endothelial cells, where binding of IL-8 may serve to promote angiogenesis[38
]. Accordingly, IL-8 expression is enhanced by vascular endothelial growth vactor (VEGF), as well as hypoxia[39
], and thus might serve as a surrogate marker for ongoing angiogenesis.
IL-8 might also serve to promote tumor cell growth and proliferation in an autocrine and/or paracrine fashion, as IL-8 expression has been documented in a number of tumor cell types, including lung[40
], and prostate cancer[45
]. In prostate cancer, recent studies showed that IL-8 expression was undetectable in androgen-sensitive cancer cell lines such as LNCaP and LAPC-4, but that IL-8 is highly expressed in the castration-resistant cell line PC-3[46
]. Transfection of prostate cancer cells with IL-8 increased both their motility and VEGF-production, correlating with increased microvessel density when transfectants were grown in immunocompromised hosts. Thus, our observation of a dichotomous IL-8 response in lenalidomide-treated patients may represent a downstream manifestation of numerous potential processes associated with prostate cancer progression.
Additionally, IL-8 levels have been shown to have prognostic value in several solid tumor types. A recent, well-powered study of patients with primary myelofibrosis showed that IL-8 levels were independently associated with survival in a multivariate analysis[47
]. These recent data support earlier data in breast cancer[48
], in which serum IL-8 levels correlated with bone marrow and lymph node involvement. Similar observations have been reported for hepatocellular carcinoma as well[49
]. An intriguing and novel mechanistic explanation for these data may be the recent observation that IL-8 drives cancer cell expression of CCR7, a chemokine receptor strongly associated with lymph node homing, and more recently associated with the stimulation of prostate cancer growth[42
In summary, the findings presented here suggest a novel mechanism for the clinical activity of lenalidomide; the induction of novel antibody specificities driven by TH2 cytokine polarization. These findings are clearly limited by the retrospective nature of the analyses performed and the small sample size, and require validation in a prospective manner. The recent development of several high-throughput antibody screening technologies for cancer patients should facilitate such investigations, both in prostate cancer and in other disease states. These data also raise the interesting possibility that circulating IL-8 levels could serve as a predictive biomarker in prostate cancer patients treated with lenalidomide. Although this hypothesis clearly requires further exploration in larger prospective trials, it is intriguing because identification of a predictive biomarker could potentially serve as an early indication of disease response to lenalidomide in prostate cancer patients, aiding clinical decision making, and possibly sparing patients from protracted treatment with agents that are not likely to alter their clinical outcome.