Towards gastric cancer immunotherapy: assessment of cancer immunity and potential immune targets

Al Khathami, Ali Gaithan (2018). Towards gastric cancer immunotherapy: assessment of cancer immunity and potential immune targets. University of Birmingham. Ph.D.

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Abstract

Gastric cancer (GC), the fourth most common malignancy worldwide, has poor prognosis and treatment innovation is needed. The aims of this project were to investigate immune targets and treatment strategies for GC. I identified new T-cell epitopes in three Epstein-Barr virus (EBV) tumor antigens, LMP1, LMP2 and BARF1, expressed in the 10% of GC cases positive for EBV. T-cell clones showed that a BARF1-specific CD4 T-cell epitope restricted by HLA-DR51, an allele common in the population, was presented by an EBV-positive epithelial cancer cell line.

Analysing blood and fresh tumor from newly diagnosed GC patients, I detected T-cell responses to MAGEA1, MAGEA4 and NY-ESO-1 tumour antigens in blood but not tumor. Compared to healthy donors, patients had: higher frequencies of LAG3 or CTLA4 positive CD8 T-cells, TIM-3 or CTLA4 CD4+ T-cells, T-regs, NKT-cells and gamma-delta T-cells in blood and tissue. Patients also had high granulocytic MDSC frequencies in PBMC. The CD4:CD8 ratio was low in some patients’ blood, potentially indicating immunosenesence, but was always higher in tumor tissue.

I successfully generated tumour infiltrating lymphocytes (TILs) from nine patients’ tumors. These comprised high T-cells and NK-cells and low T-reg and MDSC. LAG-3 was increased, but PD1, was decreased on TIL T-cells. Using 3-dimensional organoids established from two patients, I showed that TIL NK-cells, but not TIL T-cells, recognized autologous tumor organoids. My results are the first proof of principle that TILs can readily be generated from gastric tumors, can target tumors cells and therefore be used to treat gastric cancer.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Supervisor(s):
Supervisor(s)EmailORCID
Taylor, GrahamUNSPECIFIEDUNSPECIFIED
Long, HeatherUNSPECIFIEDUNSPECIFIED
Licence: All rights reserved
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Cancer and Genomic Sciences
Funders: Other
Other Funders: King Khalid University
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
URI: http://etheses.bham.ac.uk/id/eprint/8855

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