# Immune Impact on Cancer Chemoresistance

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $613,838

## Abstract

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.

## Key facts

- **NIH application ID:** 9839490
- **Project number:** 5R01CA211016-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** WEIPING ZOU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $613,838
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839490

## Citation

> US National Institutes of Health, RePORTER application 9839490, Immune Impact on Cancer Chemoresistance (5R01CA211016-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9839490. Licensed CC0.

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