Cytokine Modified Macrophages

Tumor associated macrophages are inversely correlated with tumor progression in human prostate cancer (104) and they may provide important antigen presenting functions in an antitumor immune response. Studies have revealed that in radical prostatectomy specimens the macrophage marker scavenger receptor A (MSR-A) was expressed in a subset of macrophages and DCs that infiltrated prostatic tissues. The majority of MSR-A positive cells were macrophages as evidenced by coexpression of CD68 and a relatively low percentage of DC were determined by expression of S100 protein. The number of MSR-A positive cells was significantly increased in prostatic intraepithelial neoplastic lesions as compared with normal prostatic tissue. In contrast, the number of MSR-A positive cells decreased with tumor progression. This reduction in the number of MSR-A positive cells seems to demarcate tumor progression as indicated by clinical and pathological correlations. These studies may also be relevant because germ line mutations in the MSR-1 gene have been associated with increased risk of prostate cancer in some (105,106) but not all (107) studies.

To develop protocols that optimize the processing and presentation of tumor antigens we isolated peritoneal macrophages from normal adult mice and transduced them with IL-12 using an adenoviral vector. Using the 178-2 BMA mouse metastatic prostate cancer model we demonstrated that in situ cell therapy with AdIL-12 transduced macrophages produced significant local tumor control, decreased metastases and improved survival compared with control Ad^-gal transduced cells (108). Quantitative immunohistochemical analysis demonstrated significantly increased infiltration of CD4+ and CD8+ T-cells in tumors injected with AdmIL-12 transduced macrophages compared with controls. Systemic immune effects were documented by enhanced splenocyte-derived NK cell activity on day 2 after AdIL-12 transduced macrophage injection and increased splenocyte-derived tumor specific cytotoxic T-lymphocyte activities on day 14. Trafficking studies with fluorescent labeled macrophages confirmed that the intratumoral injected AdIL-12 transduced macrophages migrated to draining lymph nodes more efficiently than Ad^-gal transduced macrophages. This novel approach to prostate cancer therapy demonstrates that cytokine modified macrophages should be considered for further studies as our preclinical studies revealed that they are capable of generating antitumor immune responses that provide effective antimetastatic activities in preclinical studies. Optimal isolation and transduction methods for macrophages need to be investigated further. However, our data demonstrated that AdIL-12 transduced murine peritoneal exudate macrophages secreted high levels of mIL-12 and showed increased surface expression of MHC class I and II and F4/80 antigen. It is also possible that other cytokines, such as RTVP-1, may also offer therapeutic enhancement in the in situ macrophage setting if they also enhance the ability of the cells to take up and process tumor antigens at the site of injection and migrate to appropriate sites such as draining lymph nodes and present antigen to downstream effector cells. As a secreted molecule, RTVP-1, like IL-12, may also have indirect benefits at the site of injection through support of effector NK and CTL cells or recruitment of additional APCs. Direct and/or indirect effects on tumor vasculature and angiogenesis may also contribute to the effectiveness of IL-12 (108) and RTVP-1 (71).

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