PD-1 and cancer: molecular mechanisms and polymorphisms

Abstract

The programmed cell death protein 1 (PD-1) is expressed by activated T cells that act as an immunoregulatory molecule, and are responsible for the negative regulation of T cell activation and peripheral tolerance. The PD-1 gene also encodes an inhibitory cell surface receptor involved in the regulation of T cell functions during immune responses/tolerance. Beyond potent inhibitory effects on T cells, PD-1 also has a role in regulating B cell and monocyte responses. An overexpression of PD-1 has been reported to contribute to immune system avoidance in different cancers. In particular, PD-1 over-expression influences tumor-specific T cell immunity in a cancer microenvironment. Blocking the PD-1/PD-1 ligand (PD-L1) pathway could potentially augment endogenous antitumor responses. Along these lines, the use of PD-1/PD-L1 inhibitors has been applied in clinical trials against diverse forms of cancer. It was believed that antibodies targeting PD-1/PD-L1 might synergize with other treatments that enhance endogenous antitumor immunity by blocking inhibitory receptor-ligand interactions. However, in all cases, the host genetic status (as well as that of the tumor) is likely to have an impact on the expected outcomes. Various investigations have evaluated the association between PD-1 polymorphisms and the risk of various types of cancer. Frequently studied PD-1 polymorphisms, PD-1.1 (rs36084323), PD-1.3 (rs11568821), PD-1.5 (rs2227981), PD-1.9 (rs2227982), and PD-1 rs7421861, and their associations in the risk of susceptibility to different types of cancer are mentioned in this review, as are studies highlighting the significance of conducting genetic association studies in different ethnic populations.

Inhibitors of the PD-1 Pathway in Tumor Therapy

“…Tumor cells can express PD-L1 and/or PD-L2, which can be induced by multiple pathways, including upregulation by cytokines, chromosomal copy gain, disruptions of the PDL1 3′ untranslated region, mutations of the genes encoding PI3K AKT, EGFR, and CDK5, MYC overexpression, and viral proteins (EBV LMP1) (40). PD-1 may restrain T cells that have been activated by tumor Ag-bearing APCs in lymph nodes, T cells trafficking to the tumor, and effector T cells within the tumor.…”

Association of programmed death‐1 gene polymorphisms with the risk of basal cell carcinoma

“…Extensive data from the literature have reported that PD‐L1 is over‐expressed in many solid tumours, including lung, breast, melanoma, lymphoma, kidney, bladder, brain, thymus, oesophagus, gastrointestinal tract and pancreas (Gatalica et al, ; Majzner et al, ; Velcheti et al, ). PD‐1 binding to PD‐L1 on different immune cells leads to inhibit immune responses against various tumours (Brahmer et al, ; Salmaninejad et al, ). Recently, genome‐wide association studies (GWAS) have suggested genetic single nucleotide polymorphisms (SNPs) in genes encoding immunosuppressive molecules participate in the failure of immune responses against tumour progression and thereby contribute to the risk of developing different tumours (Chahal et al, ; Li, Liang, Vivo, Tang, & Han, ).…”

Immunoterapia z użyciem przeciwciał monoklonalnych ukierunkowanych na szlak PD-1/PD-L1 w chorobach nowotworowych

“…Ekspresja PDL2, w porównaniu do PDL1, nie jest tak powszechna i ogranicza się do makrofagów, komórek dendrytycznych, oraz niektórych subpopulacji limfocytów B [28,36,37]. Wykazano również częściową obecność PDL2 na komórkach tucznych pochodzenia szpikowego, limfocytach T oraz na komórkach śródbłonka naczyniowego [25,38].…”

“…[93,94]. Ostatnie badania wykazały, że polimorfizm PD1.3 jest regulatorowym SNP, którego obecność wiąże się z wyższą podatnością zachorowania na raka jelita grubego [38]. Polimorfizm ten może również zmieniać wiązanie czynnika transkrypcyjnego 1 (runt-related transcription factor 1 -RUNX1) oraz modyfikować regulację transkrypcyjną genu PDCD1 [95].…”