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Immune infiltration in ovarian cancer and its significance in chemotherapy

University of British Columbia

High grade serous carcinoma (HGSC), the most commonly diagnosed ovarian cancer subtype, is often presented as late stage disease with high recurrence rates, thus contributing to poor prognosis. Despite poor survival outcomes, the presence of tumour-infiltrating lymphocytes (TIL) in primary, untreated tumours is associated with increased survival. However, little is known about the phenotype and composition of TIL subsets in HGSC patients following treatment. In this thesis, we investigated the functional phenotype of TIL and the changes in immune composition in tumours over the course of chemotherapy. In Chapter 2, we investigated the association of cytotoxic TIL with the presence of apoptotic tumour cells in primary tumours. By immunohistochemistry (IHC), we found that the majority of the CD8⁺T cells lack cytotoxic Ganzyme B and that the presence of both CD8⁺ and Granzyme B⁺TIL were not associated with the presence of apoptotic cleaved caspase-3⁺ tumour cells. In Chapter 3, we investigated the composition of TIL subsets in HGSC following neoadjuvant chemotherapy in matching pre- and post-chemotherapy tumour samples. By IHC, we found an increased density of intraepithelial T cells, CD20⁺B cells, and TIA-1⁺ and PD-1⁺TIL. In contrast, no significant change was found in the density of intraepithelial Granzyme B⁺TIL, FoxP3⁺T cells, or CD68⁺ macrophages. Patients with high CD8⁺TIL density following chemotherapy showed prolonged survival. Thus, we found the immune response to cancer is dynamic, and TIL populations change during the course of treatment. The results from this study indicate chemotherapy can alter the immunologic microenvironment in which tumour prior to chemotherapy lacking cytotoxic T cells can have increased infiltration of cytotoxic T cells and B cells, as well as PD-1⁺TIL. This study indicates the increased TIL infiltration following chemotherapy could be further enhanced with immunotherapies, such as tumour-specific vaccines and immune modulators (PD-1 blockade), to eradicate remaining tumour cells and reduce recurrences in HGSC. This work contributes to a better understanding of the effects of chemotherapy on TIL and this can lead to a more strategic development of immunotherapies in order to harness the anti-tumour immune response and mitigate immunosuppression against cancer.

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2015-02-25

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/52275

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/