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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies with a five-year survival rate of only 9%
Ozdemir et al showed that deficiency of α-smooth muscle actin (α-SMA)+ myofibroblasts in stroma resulted in concentrated Treg and decreased Teff in PKT (Ptf1a-Cre; LSL-KrasG12D; Tgf-βr2flox/flox) mice which were corroborated by the human data that PDAC with low number of myofibroblast was associated with shorter survival [19]
T-cell maintenance compared with WT. These findings indicate that TOX serves as a supporting factor for the tumor antigen-specific Tc to persist in the tumor environment and a self-protection mechanism from overstimulation and dying
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies with a five-year survival rate of only 9%. The desmoplastic dense stroma [3], bearing relatively low mutational loads, the low number of tumor neoantigens [4,5], the poor tumor immunogenicity [6,7], acquired tumor. Cancers 2020, 12, x intrinsic therapy resistance, genetic and epigenetic instabilities, and the unique immunosuppressive mutational loads,the low number of tumor neoantigens [4,5], the poor tumor immunogenicity [6,7], tumor microenvironment (TME) are the proposed characteristics for the impaired drug delivery and acquired tumor intrinsic therapy resistance, genetic and epigenetic instabilities, and the unique low therapy response. Immunosuppressive tumor microenvironment (TME) are the proposed characteristics for the impaired drug pancreatic delivery and TME low therapy response. Dysfunctionality of antitumor immune response, including the exhaustion of T lymphocytes [8]
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