Exhausted CD4+ T cells revealed the increased expression of genes related to cell cycle, angiogenesis, and cytokines. During the process of exhaustion, restimulated CD4+ T cells exhibited altered expression of (A) cell cycle inhibitor p21, which was strongly elevated in CD4+ T cells cocultured with cancer cells, (B) upregulation of angiogenesis-related genes, and (C) overexpression of interleukins IL-6 and IL-1B only in CD4+ T cells co-cultured with cancer cells. (D) The highly elevated intracellular levels of IL-6 and IL-1B were found only in T cells co-cultured with cancer cells (T15M). (A) The data from 3 independent biological replicates (donors) are presented. (B,C) The data are from 1 representative biological replicate, the other biological replicates are presented in Figure S7. The statistical significance was calculated using Student’s t-test p < 0.05 and statistically significant values are indicated by asterisks. The uncropped blots and molecular weight markers are shown in Supplementary Materials.