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Title: T cells in HBV associated hepatocellular carcinoma and other cancers
Author: Li, Xi
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Individuals with HBV associated hepatocellular carcinoma or other cancers are characterized by dysfunctional anti-virus and anti-tumor T-cell responses. Since noteworthy benefits of inhibitory pathway blockades, such as PD-1 inhibitor or CTLA-4 inhibitor have been achieved in multiple advanced cancers, the next critical question is which mono- or combinatorial blockade regimens may reinvigorate anti-virus and anti-tumor T-cell immunity in multiple cancers. This thesis aims to comprehensively characterize the expression patterns of 8 known inhibitory receptors on T cells in order to provide a rationale for the design of next generation blockade immunotherapy to benefit to more individuals with advance cancers. This thesis has shown that PD-1 and Tim-3 are significantly up-regulated on both CD4 and CD8 TILs when comparing to its expression on PBMCs in 19 paired PBMCs-TILs HBV associated HCC and 39 breast cancer individuals. This indicates PD-1 and Tim-3 blockade may be a promising target in HBV associated HCC and breast cancer immunotherapy. Furthermore, the combinatorial expression analysis of the co-expression of PD-1, CTLA-4, 2B4, KLRG-1 and TIGIT identifies 2B4+KLRG-1+TIGIT+PD-1-CTLA-4- as the dominant phenotype of CD8 TILs in HBV associated HCC; 2B4+KLRG-1-TIGIT+PD-1+CTLA-4-and as the shared dominant phenotypes of CD8 TILs in breast cancer, gastric cancer, esophageal cancer, colorectal cancer, lung cancer and renal cancer individuals. Our data indicates that the combinatorial blockade of additional pathways such as 2B4, TIGIT and KLRG-1along with PD-1 pathway may increase the overall response rate in multiple cancer immunotherapy. Furthermore, this thesis also identified the positive correlation between PD-1 expression on TILs and PD-L1 expression in tumors from non-triple negative breast cancer individuals. It indicates that PD-L1 may have the value as a biomarker in selecting patients who may benefit from PD-1 pathway blockade in non-triple negative breast cancer individuals. In addition, this thesis also applied multiple bioinformatics algorithms to identify the distinctive expression of inhibitory receptors on T-and NK-cells in PBMCs from a cross-sectional chronic HBV cohort (N=66). The hierarchical clusters in the CITRUS algorithm showed down-regulation of 2B4 on the CD3+CD8+CD56+ subset in HBV-associated cirrhosis individuals when compared with chronically infected individuals and healthy donors. In parallel, the CITRUS algorithm also identified reduced co-expression of 2B4 and TIGIT on the CD3-CD8+CD56+ subset in HBV-associated cirrhosis and HBV-associated HCC when compared with healthy donors. The mono- or combinatorial down- regulation of 2B4 and TIGIT may indicate the activation of NKT cells and NK cells respectively in the late stages HBV-associated disease (cirrhosis and HCC subgroups), which may have an important role in HBV-associated disease progression, although more functional studies are necessary to confirm this finding.
Supervisor: Dong, Tao ; McMichael, Andrew Sponsor: CSC-Oxford University Scholarship
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available