Abstract 410: NLRP3 is involved in tumor development by regulating immune function

Abstract

Abstract The NLRP3 inflammasome is a multiprotein cytoplasmic complex that mediates the processing of pro-inflammatory interleukin-1β (IL-1β), IL-18 and possibly IL-33, via the activation of Caspase-1. While NLRP3 has been widely described in the pathogenesis of inflammatory diseases, its role in tumor-host interactions, where inflammation is known to be a major player, has yet to be fully elucidated. We observed that DMBA carcinogen treatment that induced large and numerous papillomas in the skin of wt mice induced barely visible lesions in NLRP3 deficient counterparts. Similarly IV injection of B16F10 melanoma cells resulted in multiple lung metastases in wt mice but virtually no metastatic growth in NLRP3-deficient animals. The NLRP3 inflammasome thus appears to be a key helper for tumor cell growth and survival at both primary and secondary sites. Bone marrow transplantation revealed that leukocyte-derived NLRP3 plays a key role in supporting tumor cell survival prompting us to compare the immune cell distribution and function in NLRP3 deficient mice to those in wt littermates, in both the presence and absence of tumor growth. Flow cytometry analysis of immune cell populations in these mice allowed us to link NRLP3 to the recruitment, adaptation and ability of the immune system to target tumor cells. We observed that compared to wt animals, NLRP3 KO mice had fewer CD3+CD4+ T cells, NK cells and F4/80+CD11c+ myeloid cells but more CD11b+Gr1+ cells, B lymphocytes and F4/80+CD206+ macrophages of the M2 phenotype in the spleen. The increased numbers of myeloid derived suppressor cells (MDSC) and M2 macrophages in mice that displayed decreased tumor growth was counterintuitive but was associated with functional impairment that could explain decreased permissiveness of the microenvironment for tumor growth. Our observations provide a framework to investigate the mechanistic implication of NLRP3 in the relationship between tumor cells and their microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 410. doi:1538-7445.AM2012-410