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Title: Mechanisms of co-stimulatory and inhibitory receptors in human cancer-specific cytotoxic T cells
Author: Bin Abd Hamid, Megat Hafizzuddin
ISNI:       0000 0004 8507 6724
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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Clinical studies have shown that the upregulation of immunocheckpoints such as PD-1 on tumor-infiltrating T lymphocytes (TILs) can impair the clinical outcome of cancer patients. However, current immunocheckpoints-targeting immunotherapies have failed to improve response in some patients and cancer types. This is likely due to the heterogeneity of the tumor immune composition, the overall complex TILs immunophenotype and the influence of the immunosuppressive tumor microenvironment. It is therefore important to assess the characteristics and mechanisms of TILs, especially cancer-specific cytotoxic CD8+ T cells (CTLs), in order to develop more effective T cell immunotherapy strategies. In this study, comprehensive assessment using paired tumor, paratumor and peripheral blood from cancer patients demonstrated concomitant upregulation of both inhibitory CD94/NKG2a receptor and its HLA-E ligand in tumor. Although their engagement has been described on NK cells, it remains unclear whether this interaction could constitute an additional immunocheckpoint of cancer-specific CTLs in cancer. We demonstrated that the engagement of NKG2a and HLA-E resulted in impaired anti-tumor cytotoxicity, cytokine production and proliferation of CTLs, which recovered following antibody-blockade treatment. In contrast, the antagonistic NKG2a and CD103 expression on TILs suggest a distinct anti-tumor role of CD103. The CD103+ cancer-specific CTLs were found to self-produce TGF-β to sustain own CD103 expression, have improved TCR antigen sensitivity, faster cancer killing and elevated energy potential. However, they are more susceptible to apoptosis after prolonged cancer exposure. In addition, we demonstrated that a sizeable portion of cancer-specific CTLs lacks IFNγ expresssion and production, and discovered that this is contributed by CpG hypermethylation of its IFNγ promoter. In summary, this study carried out in-depth investigation into the impacts of the inhibitory receptor NKG2a, costimulatory receptor CD103, and epigenetic DNA methylation, on anti-tumor T cell responses. The thorough understanding of these key factors in affecting cancer-specific CTL functions and their restoration potential, could be important for future designs of more effective cancer immunotherapy strategies.
Supervisor: Peng, Yanchun ; Dong, Tao Sponsor: Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Cancer Immunology