Mapping of Ovarian Cancer Tumor Cell Microenvironment Highlights Key Role of T Cells

BUFFALO, N.Y. — Understanding the chemokine landscape of papillary serous ovarian cancer, the most common form of the disease, is important for the development of new immunotherapy strategies where the goal is to increase the presence and function of T cells in the tumor microenvironment. New research examining the molecular environment of ovarian cancer is the first to map the presence of chemokines, immune-system proteins that mobilize T cells in this disease. The study was conducted at the Perelman School of Medicine at the University of Pennsylvania and led in part by Emese Zsiros, MD, PhD, FACOG, a Penn fellow at the time the research was conducted and now an Assistant Professor in the Department of Gynecologic Oncology at Roswell Park Comprehensive Cancer Center. Findings have been published online ahead of print in the journal Clinical Cancer Research.

“Ovarian cancer patients who have T cells within their tumor at the time of diagnosis live significantly longer. These patients show an immune response to their disease, which slows down tumor progression and recurrence,” said Dr. Zsiros. “The trafficking of T cells and other immune cells is mainly governed by chemokines, which are small signaling proteins that determine cell migration.”

In this study, T cells were equipped with chemotherapy agents that target metastases in a complex multistep process. The ability of these re-engineered T cells to infiltrate is regulated by patients’ own tumors and their chemokine environment. In their analysis of the papillary serous ovarian cancer environment, researchers found that, for a significant number of patients, the chemokine landscape is very diverse but exhibited a high number of known T cells that recruit chemokines.

Successful immunotherapy depends on the ability of the re-engineered T cells to travel into the tumor environment. The scientists also report that tumors lacking T cells also may express some of these quasi-universal chemokines. The challenge is to manipulate the ovarian cancer chemokine landscape in a way that promotes recruitment of tumor-specific T cells, while repressing the recruitment of other immune cells that dampen the patient’s antitumor response.

Researchers also report that the ovaries, the primary disease site for these tumors, have the same chemokine expression as metastatic deposits outside the pelvis — an important factor to consider when designing immunotherapy trials targeting chemokines or chemokine receptors on T cells.

“Chemokines are important regulators of circulation, homing and retention of T cells, and thus the characterization of the tumor chemokine microenvironment is key to developing effective immunotherapy against solid tumors such as ovarian cancer,” said principal investigator and senior author George Coukos, MD, PhD, faculty leader in tumor biology at the Ludwig Centre of the University of Lausanne. Dr. Coukos is an adjunct professor of Obstetrics and Gynecology at the Perelman School of Medicine at the University at Pennsylvania, where this research was conducted.

Roswell Park researchers will continue to focus on developing and testing new chemokine and chemokine-receptor-blocking agents to enhance the patients’ own immune response with a goal of achieving longer survival and better quality of life for patients diagnosed with ovarian cancer.

The study title is “The Ovarian Cancer Chemokine Landscape is Conducive to Homing of Vaccine-primed and CD3/CD28 Costimulated T cells Prepared for Adoptive Therapy.”

This work was supported by three National Cancer Institute (NCI) grants: P50CA83638, a Specialized Programs of Research Excellence (SPORE) award, R01FD003520 and R01CA127334. Additional support was provided by the Ovarian Cancer Research Fund and the Conquer Cancer Foundation of the American Society of Clinical Oncology.

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