Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

dc.contributor.authorSaka, Didem
dc.contributor.authorGokalp, Muazzez
dc.contributor.authorPiyade, Betul
dc.contributor.authorCevik, Nedim Can
dc.contributor.authorSever, Elif Arik
dc.contributor.authorUnutmaz, Derya
dc.contributor.authorCeyhan, Guralp O.
dc.contributor.authorDemir, Ihsan Ekin
dc.contributor.authorAsimgil, Hande
dc.date.accessioned2023-02-21T12:34:50Z
dc.date.available2023-02-21T12:34:50Z
dc.date.issued2020-01-01
dc.description.abstractT-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.
dc.description.issue8
dc.description.issueAUG
dc.description.volume12
dc.identifier.doi10.3390/cancers12082274
dc.identifier.urihttps://hdl.handle.net/11443/1822
dc.identifier.urihttp://dx.doi.org/10.3390/cancers12082274
dc.identifier.wosWOS:000579052100001
dc.publisherMDPI
dc.relation.ispartofCANCERS
dc.subjectpancreatic ductal adenocarcinoma
dc.subjectPDAC
dc.subjectT-cell exhaustion
dc.subjectepigenetics
dc.subjectThymocyte selection-associated high mobility group box protein
dc.subjectTOXs
dc.subjecttumor microenvironment
dc.subjectTME
dc.titleMechanisms of T-Cell Exhaustion in Pancreatic Cancer
dc.typeArticle

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