UC San Diego

Cancer immunoediting is the process whereby immune cells protect against cancer formation and sculpt the immunogenicity of developing tumors. In its most complex form, this process involves the initial elimination of highly immunogenic tumor cells from an unedited heterogeneous cell repertoire, followed by the eventual escape of non-immunogenic, edited cells. Edited cell lines, which are derived from tumors that develop in wild-type (WT) mice, are termed progressors because they are poorly immunogenic and grow progressively when transplanted into syngeneic naïve WT mice. Unedited cell lines, which are derived from immune deficient mice, are often highly immunogenic and are termed regressors because they are rejected when transplanted into syngeneic naïve WT mice. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting, and the molecular differences between regressor and progressor tumors remain largely undefined. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3¿ methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2-/-, and RAG2-/- x [gamma]c-/- mice. We found that innate immune cells could indeed manifest cancer immunoediting activity in the absence of adaptive immunity. While natural killer (NK) cells can directly edit the natural killer group 2D (NKG2D) ligand H60a when expression levels are heterogenous within a tumor, these cells also indirectly edit through the production of IFNg by polarizing M1 macrophages, which act as important effectors during cancer immunoediting. Using a non-biased microarray approach, we found that interleukin 17D (IL- 17D) expression in tumors leads to the recruitment of NK cells through indirect production of MCP-1, which mediates the rejection of progressor tumors and leads to priming of the adaptive immune system and subsequent immunological memory of the host. All together these studies showcase the central role of NK cells in both cancer immunoediting and elimination, and implicate a novel tumor secreted factor IL-17D for use in tumor immunotherapy