Abstract 1537: Characterization of tumor-infiltrating macrophages in humanized mouse model of prostate cancer.

Abstract Macrophage infiltration is observed in many types of human and mouse malignant tumors. Though some studies reported anti-tumor activity of tumor-associated macrophages (TAM) the majority of reports revealed contribution of TAM to tumor growth, invasion and metastasis. The phenotype and functions of TAM in prostate cancer are not well known. However, their abundance in the tumor suggests an important role in the course of malignant progression. In our novel humanized mouse model of prostate cancer, the expression of human HLA-DR*1501 (DR2b) transgene drastically impairs immune response to prostate tumor and induces excessive accumulation of TAM, which predominate in tumor tissue. In parallel, substantial accumulation of CD4+CD25+FOXP3+ T cells is observed in the tumor mass. The initial gene expression profiling of TAM in DR2b+ mice revealed their mixed M1/M2 phenotype since these cells expressed typical M2-associated genes TGFβ, IL10, arginase I, stabilin-1 and M1-associated genes IL1β, TNFα and IL6. Moreover, TAM strongly expressed chemokines CCL2, CCL3, CCL4, CCL5 and CXCL10, which are capable to recruit myeloid, NK and T cells as well as immune checkpoint receptor PDL-1. Interestingly, compared to DR2b- mice, TAM from DR2b+ animals had reduced expression of important NK and T cell survival factor IL15. Immunohistochemical investigation of the tumor tissue revealed that CD68+ TAM co-localized with T cells on the periphery of the tumor and expressed M2-associated marker stabilin-1. Moreover, T cells were found exclusively on the tumor periphery, whereas TAM were observed inside tumor mass. Altogether, present data suggest that TAM in DR2b model of prostate cancer have potential to recruit various immune cells to the tumor mass. However, elevated expression of immunosuppressive factors TGFβ, IL10, arginase I, PDL-1 and close association between TAM and T cells on tumor periphery may impair T cell activation and induce generation of Tregs. Citation Format: Vladimir Ryabov, David Kim, Rikka Saito, Richard B. Alexander, Elena Klyushnenkova. Characterization of tumor-infiltrating macrophages in humanized mouse model of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1537. doi:10.1158/1538-7445.AM2013-1537