ICOS limits memory-like properties and function of exhausted PD-1+ CD8 T cells [ATAC-seq]

During persistent antigen stimulation, PD-1+CD8 T cells are maintained by progenitor exhausted PD-1+TCF-1+CD8 T cells (Tpex). Tpex respond to PD-1 blockade, and regulation of Tpex differentiation into more functional Tex is of major interest for cancer immunotherapies. Tpex express high levels of Inducible Costimulator (ICOS), but the role of ICOS for PD-1+CD8 T cell responses has not been addressed. In chronic infection, ICOS-deficiency increased both number and quality of virus-specific CD8 T cells, with accumulation of effector-like Tex due to enhanced survival. Mechanistically, loss of ICOS signaling potentiated FoxO1 activity and memory features of Tpex. ICOS-deficient Tex displayed enhanced survival and improved cytokine production. In chronically-infected mice, ICOS-Ligand blockade expanded effector-like Tex, reduced viral load and potentiated anti-PD-L1 therapy. In a mouse model of hepatocellular carcinoma, ICOS inhibition improved cytokine production by tumor-specific PD-1+CD8 T cells and sensitized tumors to PD-1 targeted therapy. Overall, we show that sustained ICOS costimulation limits CD8 T cell responses during chronic antigen exposure. Overall design: P14 (LCMV-specific CD8 T cell) electroporated with Cas9/gRNA control or targeting Icos were transfered into mice prior to LCMV c13 infection. Once mice are chronically infected (>42DPI), 2 to 3 mice were pooled per experimental replicate for CD8 T cell isolation from spleen. Progenitor Tpex (CD39neg PD1+) and differentiated Tex (CD39+ PD1+) P14 control or sgICos were sorted for ATACseq profiling.