393 Myeloid cells alter their effector status in response to the secretome of senescent cancer cells

Abstract

Cellular senescence plays an important role in tissue development, homeostasis and cancer control. It is characterized by a G0/G1 arrest of the cell cycle, stop in proliferation and induction of senescence associated ß-galactosidase activity thereby promoting aging or tissue degeneration and possibly restraining cancer. We recently found in RIP1-Tag2 mice that the cytokines IFNy and TNF, exogenously delivered by immune cells, can arrest cancer growth through the induction of cellular senescence. Thus, in addition to cancer control through killing, the immune system can arrest a variety of human and mouse cancer cells by inducing senescence. However, senescent cancer cells may also become potentially harmful due to their secretory phenotype. Here we analyzed the effect of the senescence associated secretory phenotype (SASP) of murine ß-cancer cells on the differentiation and function of macrophages. ß-cancer cells driven into senescence via IFNy and TNF show a highly inflammatory SASP. Enhanced secretion of cytokines like CCL2, CCL5, CXCL9 or CXCL10 attracts immune cells and modulates their function. The SASP attracted bone-marrow derived macrophages (BMDM) and altered their polarization status and function. The SASP induced migration and polarization towards a M2-like phenotype in BMDMs. Such M2-like macrophages are characterized by lack of iNOS and concurrent increase in arginase1 protein levels. Simultaneously the BMDMs lost their naïve status and showed a decreased phagocytic ability, supporting the concept that antigen presenting cells transform from naïve phagocytizing to effector cells during maturation. Furthermore we showed that non-senescent tumor cells increased proliferation if challenged with the SASP and SASP-chemokines. These data underline that the removal of senescent cancer cells from the organism may be an important cancer-protective mechanism. Taken together, modulating the secretome of senescent cancer cells may change the tumor microenvironment, trigger different anti-tumor immune responses and directly affect the immune responses to non-senescent cancer cells.