Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Abstract

T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.

Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy

“…IFN-γ is a major mediator inducing the death of tumor cells. However, continuous exposure to IFN-γ also stimulates tumor cells to express multiple inhibitory modulators including PD-L1 which are majorly enriched in C2 and C3 in our study, thereby suppress the secretion of IFN-γ by effector T cells and result in T cell exhaustion [24,25]. Together, a more prominent feature of immunosuppression may be promoted by these features of C2 and therefore the prognosis of C2 is worse.…”

Preoperative Controlling Nutritional Status (CONUT) score predicts short-term outcomes of patients with gastric cancer after laparoscopy-assisted radical gastrectomy

“…Lymphocytes are important cellular components of the human immune response system that help to fight tumours by inhibiting cancer cell proliferation, invasion and migration [ 30 ]. Saka et al [ 31 ] reported that T cell exhaustion was closely associated with poor prognosis in cancer. Cholesterol plays a vital role in modulating the activity of membrane proteins, which may be associated with the occurrence and development of cancer and interactions with the body’s immune system.…”

Identification of Prognostic Stromal-Immune Score–Based Genes in Hepatocellular Carcinoma Microenvironment

“…It is worth reminding that our results did not contradict previous findings that high infiltration of CD8 + T cells indicated beneficial prognosis, but extended and enriched this conclusion. In the recent literature, tumor with higher CD8 + T cell infiltration, but T cell dysfunction and increased immune escape result in a poor prognosis ( Hossain et al, 2020 ; Saka et al, 2020 ).…”