Polyfunctional KLRG-1+CD57+ Senescent CD4+ T Cells Infiltrate Tumors and Are Expanded in Peripheral Blood From Breast Cancer Patients

Abstract

Senescent T cells have been described during aging, chronic infections, and cancer; however, a comprehensive study of the phenotype, function, and transcriptional program of this T cell population in breast cancer (BC) patients is missing. Compared to healthy donors (HDs), BC patients exhibit an accumulation of KLRG-1+CD57+ CD4+ and CD8+ T cells in peripheral blood. These T cells infiltrate tumors and tumor-draining lymph nodes. KLRG-1+CD57+ CD4+ and CD8+ T cells from BC patients and HDs exhibit features of senescence, and despite their inhibitory receptor expression, they produce more effector cytokines and exhibit higher expression of Perforin, Granzyme B, and CD107a than non-senescent subsets. When compared to blood counterparts, tumor-infiltrating senescent CD4+ T cells show similar surface phenotype but reduced cytokine production. Transcriptional profiling of senescent CD4+ T cells from the peripheral blood of BC patients reveals enrichment in genes associated with NK or CD8+-mediated cytotoxicity, TCR-mediated stimulation, and cell exhaustion compared to non-senescent T cells. Comparison of the transcriptional profile of senescent CD4+ T cells from peripheral blood of BC patients with those of HDs highlighted marked similarities but also relevant differences. Senescent CD4+ T cells from BC patients show enrichment in T-cell signaling, processes involved in DNA replication, p53 pathways, oncogene-induced senescence, among others compared to their counterparts in HDs. High gene expression of CD4, KLRG-1, and B3GAT1 (CD57), which correlates with increased overall survival for BC patients, underscores the usefulness of the evaluation of the frequency of senescent CD4+ T cells as a biomarker in the follow-up of patients.

CD39+conventional CD4+T cells with exhaustion traits and cytotoxic potential infiltrate tumors and expand upon CTLA-4 blockade

“…In this regard, one limitation of our analysis is that it does not dismiss the contribution of CD39 + expression in CD8 + T cells. However, our previous observation that BC tumors exhibit greater proportions of TI-CD4 + than CD8 + T lymphocytes 21 supports the relevance of the contribution of the CD39-expressing CD4 + T cell in overall survival.…”

“…TFs (intracellular staining) and intracellular cytokine detection cells were performed following protocols previously described 16, 21 .…”

Ascitic Senescent T Cells Are Linked to Chemoresistance in Patients With Advanced High-Grade Serous Ovarian Cancer

“…In line with previous studies, patients with HGSOC showed elevated frequency of Tsen CD8 + T cells in the peripheral blood compared with age-matched HDs. In patients with breast cancer, the frequency of Tsen CD4 + T cells was also significantly increased ( 27 ). However, in patients with HGSOC, the frequency of Tsen CD4 + T cells in the peripheral blood was comparable to HDs (data not shown).…”

Cytokine-Induced Senescence in the Tumor Microenvironment and Its Effects on Anti-Tumor Immune Responses

“…In breast cancer patients, killer cell lectin-like receptor G1 (KLRG-1) + CD57 + CD4 + and CD8 + senescent T cells that produce more effector cytokines, granzyme B and perforin accumulate in peripheral blood and in the tumor. The expression of CD4, KLRG-1, and CD57 correlates with increased overall survival for breast cancer patients [139]. Contrary to the beneficial role of KLRG-1 + CD57 + CD4 + senescent Th cells in breast cancer patients, Ye et al showed that tumor-derived γδ T cells induce senescence in CD4 + T cells and also in DCs that were no longer able to process and present tumor antigens to T cells.…”