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.

Renal cell carcinoma (RCC) represents around 2-3% of all malignancies diagnosed in adult patients. Most frequent (around 70-80% cases) and the most aggressive subtype is clear cell RCC (ccRCC). Mutations in VHL (von Hippel Lindau) gene, characteristic for this cancer type, lead to altered activity of the trimeric VBC (pVHL-elongin B-C) complex and consequently to HIF-1α stabilization. In this study, we present results of exhaustive investigation of HIF-1α alternative transcript variants abundance in A498, CAKI-1, and 786-O ccRCC cell lines. We proved the existence of truncated HIF-1α protein form (HIF1AΔ-6) in A498 and HIF1A gene rearrangements in 786-O cell lines. Subsequently, we found that HIF1AΔ2-6 was more stable than the full-length HIF-1α. Moreover, the shorter HIF-1α was insensitive for hypoxia and was overaccumulated after proteasome inhibitor treatment indicative of potential diversified roles of full-length and truncated HIF-1α forms in the cell. We also showed that A498, CAKI-1, and 786-O exhibit differential expression of various regulatory genes involved in the control of metabolic processes, that is, glucose and lipid metabolism, and encoding subunits of such machineries like SWI/SNF chromatin remodeling complex. Furthermore, these cell lines exhibited differential responses to axitinib, everolimus, and sunitinib-anticancer drugs-in normoxia and hypoxia as well as various alterations in metabolism-related Abbreviations: 2-OG, 2-oxoglutarate; ALDO, aldolase; ARD1, arrest-defective 1 acetyltransferase; ARNT, aryl hydrocarbon receptor nuclear translocator; bHLH, basic helix-loop-helix; ccRCC, clear cell renal cell carcinoma; CPT1A, carnitine palmitoyltransferase 1A; CUL2, cullin 2; DFO, deferoxamine; DMOG, dimethyloxaloglycine; ENO, enolase; EPAS1, endothelial PAS domain protein 1; EPO, erythropoietin; FBP1, fructose-1,6-bisphosphatase 1; FIH-1, factor inhibiting HIF-1; G6P, glucose-6-phosphatase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HIF1A, hypoxia inducible factor 1A; HK, hexokinase; HPH, HIF prolyl hydroxylase; HRE, hypoxia-responsive element; iNOS, inducible nitric oxide synthase; LDHA, lactate dehydrogenase A; PAS, Per-ARNT-Sim; PHD, prolyl hydroxylase; PLIN2, perilipin 2; PKM2, pyruvate kinase M2; RBX-1, Ring box 1; RCC, renal cell carcinoma; SMARCB1 (INI1), SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1; TCEB1, transcription elongation factor B (SIII); VHL, von Hippel-Lindau.

No abstract

No abstract