IL-12 and IL-18 can non-redundantly improve effector functions of in vitro-generated exhausted CD8+ T Cells 2389

Abstract Description T cell receptor (TCR) stimulation by tumor antigen promotes CD8+ T cell activation and synthesis of effector molecules (e.g., IFNg, perforin, granzyme B) essential for tumor cell killing. However, chronic TCR stimulation causes T cells to become dysfunctional and unable to clear tumors. The development of these exhausted T cells (Tex) is characterized by loss of transcription factors (e.g. T-bet, Batf), that drive effector molecule expression, and increased expression of TOX, which reinforces the dysfunctional state. Cytokines can have a key role in regulating T cell effector responses, specifically IL-12 & IL-18 combination can enhance IFNg synthesis in non-exhausted T cells, but it is unclear if this occurs in Tex cells. Here, we tested the impact of IL-12/IL-18 on Tex in an in vitro chronic antigen stimulation model. IL-12 or IL-18 alone increased IFNg, perforin, and granzyme B synthesis compared to untreated Tex. Moreover, IL-12 & IL-18 combination further increased IFNg, perforin, and granzyme B synthesis and tumor killing compared to IL-12 or IL-18 alone. The combination also induced T-bet and Batf expression while downregulating TOX, suggesting these transcription factors may be driving the heightened Tex effector state. Similar results were obtained following ex vivo stimulation of mouse intratumoral CD8+ Tex. Thus, IL-12 & IL-18 may synergistically enhance bone fide Tex function and could be used as a novel treatment to better control cancer patient tumor burden. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)