Death rates attributable to ovarian cancer have been largely unchanged for decades. Although the initial response of ovarian cancer to surgical debulking and chemotherapy with platinum-based drugs is often excellent, relapse with drug-resistant cancer usually occurs and patients succumb to their disease. Patients with ovarian cancer are NOT highly responsive to current immunotherapy including PD-L1 and PD-1 blockade. Platinum-based drugs remain the major and first line chemotherapy for these patients. Thus, there is a great need to understand from a novel angle the specific cellular and molecular mechanisms by which platinum resistance occurs in patients with ovarian cancer. The tumor microenvironment is the primary arena in which tumor cells and the host immune system interact. Characterization of the nature of immune responses in the human cancer microenvironment holds the key to understanding protective tumor immunity and empowering and improving current cancer immunotherapy. Our preliminary data have shown that the interaction between CD8+ T cells and fibroblasts shapes ovarian cancer chemoresistance. Based this novel and surprising finding, we propose that the human cancer microenvironment ALSO holds the key to understanding and reversing the nature of chemoresistance in ovarian cancer. Accordingly, we hypothesize that the cross-talk between T cells, stromal fibroblasts and tumor cells plays an important role in the development of drug resistance. To test this central hypothesis, in this application, we will focus on patients with high-grade serous ovarian carcinoma, which is the most common histologic subtype, and most lethal among epithelial ovarian carcinomas. We will dissect how the interaction between CD8+ T cells and fibroblasts contributes to chemoresistance in patients with ovarian cancer. We have designed 3 relatively independent but mechanistically intertwined aims to test our central hypothesis.
Aim 1 is to test our hypothesis that ovarian cancer associated fibroblasts (CAFs) induce platinum resistance through controlling glutathione (GSH) and its metabolites.
Aim 2 is to test our hypothesis that the interaction between CD8+ T cells and CAFs affects ovarian cancer chemoresistance.
Aim 3 is to explore the molecular mechanisms and evaluate clinical and biological associations between CAFs and CD8+ T cells in ovarian cancer chemoresistance. The proposal investigates a real human disease, links tumor immunology to tumor cell biology, biochemical metabolism and chemotherapy, and addresses their mechanistic and clinical associations in the tumor environment, and tackles a significant clinical problem. The proposal is highly scientifically and clinically significant and will pave the way for novel clinical trials in the field.

Public Health Relevance

Patients with ovarian carcinoma including high-grade serous carcinoma are weakly responsive to the PD-L1 and PD-1 pathway blockade. Platinum-based chemotherapy remains the major therapy as well as the first line chemotherapy for patients with high-grade serous ovarian carcinoma. Unfortunately, ovarian cancer patients die because of chemoresistance. We fail to improve their long-term survival despite our best efforts with currently available (particularly cisplatin-based chemotherapy) therapies. There is a great need to understand from a novel angle the key cellular and molecular mechanisms by which chemoresistance and tumor relapse occur in patients with ovarian cancer. Chemoresistance is assumed to be tumor genetic and biological issues. Based on our understanding of the critical importance of the tumor immune microenvironment in guiding and improving our current immunotherapy, the published information on tumor associated fibroblasts and effector T cells, we hypothesize that the human cancer immune microenvironment holds the key to understanding and reversing the nature of chemoresistance and to improving current cancer chemotherapy. Accordingly, we will investigate the cross-talk between T cells, stromal cells and tumor cells and determine the role and mechanisms of this cross-talk in the development of cisplatin resistance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA211016-02
Application #
9397538
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Sommers, Connie L
Project Start
2017-01-01
Project End
2021-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Yu, TaChung; Guo, Fangfang; Yu, Yanan et al. (2017) Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy. Cell 170:548-563.e16
Wang, Weimin; Kryczek, Ilona; Dostál, Lubomír et al. (2016) Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer. Cell 165:1092-1105
Nagarsheth, Nisha; Peng, Dongjun; Kryczek, Ilona et al. (2016) PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer. Cancer Res 76:275-82