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Simple Summary: Growing tumors induce an immune response. For proper immune response, both CD8+ and CD4+ effector T cells are required. Tumors avoid attacks from tumor-infiltrating lymphocytes (TILs) via induction of several inhibitory signals, such as PD-L1/2, which bind to the PD-1 receptor, consequently leading to T cell dysfunction, exhaustion, and apoptosis. The mechanism of T cell exhaustion has been studied mostly in CD8+ T cells, although some results suggest that CD4+ effector T cells also undergo exhaustion. In this study, we analyze global transcript profiling, PD-1 and PD-L1 expression, and chromatin status on the PD-L1 locus. We find that in exhausted CD4+ T cells, the levels of PD-L1 are increased at both the transcript and protein levels, while PD-L1 expression depends on SWI/SNF chromatin remodeling and PRC2-repressive complexes. The expression of PD-L1 in exhausted CD4+ T cells can be reversible. Growing tumors avoid recognition and destruction by the immune system. During continuous stimulation of tumor-infiltrating lymphocytes (TILs) by tumors, TILs become functionally exhausted; thus, they become unable to kill tumor cells and to produce certain cytokines and lose their ability to proliferate. This collectively results in the immune escape of cancer cells. Here, we show that breast cancer cells expressing PD-L1 can accelerate exhaustion of persistently activated human effector CD4+ T cells, manifesting in high PD-1 and PD-L1 expression level son T cell surfaces, decreased glucose metabolism genes, strong downregulation of SWI/SNF chromatin remodeling complex subunits, and p21 cell cycle inhibitor upregulation. This results in inhibition of T cell proliferation and reduction of T cell numbers. The RNAseq analysis on exhausted CD4+ T cells indicated strong overexpression of IDO1 and genes encoding pro-inflammatory cytokines and chemokines. Some interleukins were also detected in media from CD4+ T cells co-cultured with cancer cells. The PD-L1 overexpression was also observed in CD4+ T cells after co-cultivation with other cell lines overexpressing PD-L1, which suggested the existence of a general mechanism of CD4+ T cell exhaustion induced by cancer cells. The ChIP analysis on the PD-L1 promoter region indicated that the BRM recruitment in control CD4+ T cells was replaced by BRG1 and EZH2 in CD4+ T cells strongly exhausted by cancer cells. These findings suggest that epi-drugs such as EZH2 inhibitors may be used as immunomodulators in cancer treatment. [ABSTRACT FROM AUTHOR]