Wistar scientists identify novel therapeutic approach to re-activate immune response against tumors

PHILADELPHIA — (June 21, 2022) — Due to the development of resistance to chemotherapy and recurring tumors, patients with ovarian cancer often have low survival rates. Therefore, new therapeutic options such as targeted therapy that boosts antitumor immunity are needed to improve ovarian cancer treatment efficacy and patient survival. 

In a research paper published today in Cancer Immunology Research, Rugang Zhang, Ph.D., deputy director of the Ellen and Ronald Caplan Cancer Center and program leader of the Immunology, Microenvironment & Metastasis Program, at The Wistar Institute, and his team identified that inhibiting therapeutic target KDM5A boosts a person’s immune response to tumors. 

“Understanding the basic mechanism guiding the infiltration of tumor-killing immune cells into the tumor microenvironment is key to leveraging the power of immune system to fight against cancer,” states Zhang. 

Sergey Karakashev, a recent postdoctoral researcher in the Zhang lab and co-author on the paper, elaborates. “Tumor infiltration with immune cells is one of the best predictors for survival and for better prognosis for ovarian cancer patients. We were interested in finding a way to increase tumor infiltration with immune cells.” he says. 

KDM5A is an oncogene that is often amplified in epithelial ovarian cancer and is known to repress multiple genes that are involved in tumor suppression. In this study, the scientists reveal the mechanism underpinning how KDM5A regulates immune cell infiltration and attack of tumors – by inhibiting genes involved in the antigen processing and presentation pathway. This biological pathway recognizes tumor cells and activates the immune system to invade and ultimately kill them. 

“Tumor cells find a way to downregulate this antigen presenting pathway, and by doing so, they evade immune surveillance. One of the main questions for this paper was ‘How we can restore the function of the antigen presentation pathway to promote immune infiltration and immune cell activation?’” Karakashev explains. 

To do this, the team conducted both in vitro and in vivo studies. In vitro, the team found that genes involved in the antigen presentation pathway were indeed upregulated when they knocked out KDM5A and saw the same results when they used a KDM5A specific inhibitor. For in vivo studies using mice and mouse ovarian cancer cells, the in vitro results were validated. According to the paper, KDM5A inhibition reduced tumor burden and improved survival of the tumor bearing mouse model. The in vivo experiments saw an increase in the presence of CD8 + cells which are the effector killing cells of the immune system. Additionally, more of these cells were activated, which means they were able to act against tumors in mice.

“This is a very early study,” Karakashev says, “We want to try more clinically relevant inhibitors of KDM5A and more models to increase the translatability of our findings to the clinic. Another interesting future direction would be to study KDM5A in other cancers as well.” The scientists hope that this paper will inspire more research into other epigenetic factors that regulate immune related pathways and see potential in combining this therapeutic target with other immune therapies to be effective against ovarian cancer. 

Zhang says, “Our findings provide a scientific framework to target KDM5A to overcome immune evasion employed by cancer cells. In addition to ovarian cancer, the pathway appears to broadly applicable to many cancer types. Thus, we believe the findings are broadly applicable and may have far-reaching implications in developing cancer immunotherapy.”

Co-authors: Heng Liu, Jianhuang Lin, Wei Zhou, Zhongping Dai, Andrew Kossenkov, Sergey Karakashev of The Wistar Institute; Renyta Moses, Ronny Drapkin from The University of Pennsylvania; Benjamin G. Bitler from The University of Colorado.

Work supported by: National Institutes of Health grants (R01CA202919, R01CA239128, and P50CA228991 to R. Zhang; K99CA241395 to S. Karakashev), the U.S. Department of Defense (OC180109 and OC190181 to R. Zhang), the Honorable Tina Brozman Foundation for Ovarian Cancer Research and the Tina Brozman Ovarian Cancer Research Consortium 2.0 (to R. Zhang), and the Ovarian Cancer Research Alliance (Collaborative Research Development Grant #596552, to R. Zhang and Ann and Sol Shreiber Mentored Investigator Award to W. Zhou). 

Publication Information: KDM5A inhibits anti-tumor immune response through downregulation of antigen presentation pathway in ovarian cancer. Cancer Immunology Research, 2022. Online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.