Cancer cells accelerate exhaustion of persistently activated human effector CD4+Tcells via SWI/SNF chromatin remodeling complex

Developing tumor avoids recognition and destruction by immune system due to immune escape. During continuous stimulation of tumor infiltrating lymphocytes (TILs) by tumor, the TILs become functionally exhausted. Thus, they become enable to kill tumor cells, to produce some cytokines and to proliferate. Here, we show that breast cancer cells expressing PD-L1 can accelerate exhaustion of persistently activated human effector CD4+Tcells, manifesting by high PD-1 and PD-L1 expression level on the cell surface, decreased glucose metabolism genes, strong downregulation of SWI/SNF chromatin remodeling complex subunits and p21 cell cycle inhibitor upregulation. It results in inhibition of T cells proliferation and T cell death. The transcriptome analysis on exhausted CD4+Tcells indicated strong overexpression of IDO1 and genes encoding pro-inflammatory cytokines and chemokines. The PD-L1 overexpression was also observed in CD4+Tcells after co-cultivation with renal cancer cell line overexpressing PD-L1 that suggests the existence of general mechanism of CD4+Tcell exhaustion induced by cancer cells. The ChIP analysis on PD-L1 promoter region indicated that the strong BRM recruitment in control CD4+Tcells is replaced by BRG1 and EZH2 in CD4+Tcells strongly exhausted by cancer cells. These findings suggest that such epi-drugs as EZH2 inhibitors may be used as immunomodulators in cancer treatment.