Senescent T cells: a potential biomarker and target for cancer therapy

Abstract

The failure of T cells to eradicate tumour cells in the tumour microenvironment is mainly due to the dysfunction of T cells. Senescent T cells, with defects in proliferation and effector functions, accumulate in ageing, chronic viral infections, and autoimmune disorders where antigen stimulation persists. Increasing evidence suggests that inducing T cell senescence is a key strategy used by malignant tumours to evade immune surveillance. In this review, we summarize the general features, functional regulation, and signalling network of senescent T cells in tumour development and highlight their potential as prognostic biomarkers in multiple cancer treatments, including chemotherapy, radiotherapy, and immunotherapy. Moreover, we discuss possible therapeutic strategies for preventing or rejuvenating senescence in tumour-specific T cells. Understanding these critical issues may provide novel strategies to enhance cancer immunotherapy.

Keywords: Senescent T cell; cancer immunotherapy; prognostic biomarkers; therapeutic targets; tumour microenvironment.

Figure 1

Signalling pathways involved in T cell senescence in the tumour microenvironment. In senescent T cells, MAPKs can be activated by DNA damage, metabolic disorders, proinflammatory cytokines, and sestrins. The activation of p38 inhibits telomerase activity and destroys mitochondria fitness which leads to DNA damage. DNA damage further activates p38, ERK, and STAT1/3 to pronounce the expression of CKIs to prevent T cell proliferation. P-p38 and p-JNK inhibit TCR signaling to form T cell specific SASPs. P-JNK also help senescent T cells gain innate-like killing capacity. ATM, ataxia-telangiectasia mutated; cAMP, cyclic adenosine monophosphate; CKIs, cyclin-dependent kinase inhibitors; CREB, cAMP response element-binding protein; ERK, extracellular signal-regulated protein kinase; hTERT, human telomerase reverse transcriptase; IFN-γ, interferon gamma; JNK, c-Jun N-terminal kinase; MAPKs, mitogen-activated protein kinases; NK, natural killer; NKRs, natural killer like receptors; PKA, phosphorylase kinase A; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype; STAT, signal transducer and activator of transcription; TCR, T-cell receptor; TNF-α, tumour necrosis factor alpha; Tregs, regulatory T cells; γH2AX, phosphorylated H2AX