04 Nov Mt. Sinai Study of Ovarian Cancer Finds Factor That Promotes Immunotherapy Resistance
MedicalResearch.com Interview with:
Dr .Baccarini
Alessia Baccarini, PhD
Assistant Professor
Dept. of Immunology and Immunotherapy (DII)
Icahn School of Medicine at Mount Sinai
New York, New York 10029
MedicalResearch.com: What is the background for this study?
Response: Ovarian cancer is characterized by a complex tumor microenvironment (TME) that significantly contributes to resistance against immunotherapy, particularly immune checkpoint blockade (ICB) therapies like anti-PD-1. Understanding the extracellular signals—such as cytokines and chemokines—that ovarian cancer cells utilize to create an immunosuppressive TME is critical for improving treatment outcomes.
Our research focuses on elucidating how these signaling factors contribute to tumor growth and immune evasion. We utilized a novel genomic functional approach called Perturb-map to study intratumoral heterogeneity (ITH) in ovarian cancer within a mouse model, allowing us to investigate the communication between ovarian cancer cells and immune cells.
MedicalResearch.com: What are the main findings?
Response: Our study identifies IL-4 as a pivotal factor produced by a small fraction of ovarian cancer cells that promotes immunotherapy resistance. We discovered that IL-4’s expression contributes to TME programming by fostering an immunosuppressive environment that limits T cell efficacy. Importantly, the loss of IL-4 resulted in a rearrangement of the TME, characterized by reduced macrophage presence and increased exhausted T cells, without affecting overall tumor growth. This suggests that even minimal IL-4 expression can create localized pockets of immunosuppression, contributing to ITH and clonal selection. These findings underscore the potential of targeting IL-4 signaling, alongside PD-1 blockade, as a therapeutic strategy to enhance treatment responses in ovarian cancer patients.
What should readers take away from your report?
Response: Our study reveals that ovarian cancer-derived IL-4 plays a crucial role in promoting immunotherapy resistance by shaping the tumor microenvironment (TME). Notably, IL-4 is produced by only a small fraction of ovarian cancer cells, yet its impact on TME programming is significant. We demonstrate that even low levels of cytokines, such as IL-4, can contribute to intratumoral heterogeneity (ITH) and create isolated microenvironments that favor immune evasion. This highlights the importance of considering not just the predominant cellular populations but also the subtle contributions of minor cell populations and their secreted factors in shaping tumor behavior and response to therapies.
Our findings suggest that targeting these low-expressing but influential cytokines may be a promising strategy to enhance immunotherapy effectiveness. We are now interested in translating our findings into clinical trials, particularly exploring the combination of anti-IL-4 and anti-PD-1 therapies in ovarian cancer patients, which we believe holds significant promise for enhancing treatment efficacy.
MedicalResearch.com: What recommendations do you have for future research as a results of this study?
Response: There is definitely a need for more study of IL-4 in ovarian cancer but also other cancers. A lot of what we know about this cytokine’s activity on macrophage was implied from in vitro studies. There are key differences though in vivo we need to be better understood. We also need to better understand the factors that promote ITH. This is a major issue in patients. It is a key reason why patients relapse or only partially respond. The technology we used, Perturb-map, allowed us to model ITH, and the findings were unexpected and interesting. We could see how cancer control of its environment allowed tumor clones to evolve independently and how ITH can emerge. There is a lot more to study on this phenomenon.
MedicalResearch.com: Is there anything else you would like to add? Any disclosures?
Response: I would like to emphasize the importance of the novel technologies in making this, and so much other research, be possible. Technology development is a pillar of biomedical research that is often taken for granted and not well supported by funding agencies – who often prefer either more basic biology or translational studies. New technologies are widely recognized once established – everyone is using CRISPR and single cell sequencing now – but not when they are being developed. This project was made possible thanks to the development of the Perturb-map spatial functional genomics platform, which itself is thanks to the development of other technologies like protein barcodes (Pro-Codes) and multiplex imaging.
Citation: Ovarian cancer-derived IL-4 promotes immunotherapy resistance
Gurkan Mollaoglu, Alexander Tepper, Chiara Falcomatà, Hunter T. Potak, Luisanna Pia, Angelo Amabile, Jaime Mateus-Tique, Noam Rabinovich, Matthew D. Park, Nelson M. LaMarche, Rachel Brody, Lindsay Browning, Jia-Ren Lin, Dmitriy Zamarin, Peter K. Sorger, Sandro Santagata, Miriam Merad, Alessia Baccarini, Brian D. Brown,
Cell,2024, ISSN 0092-8674,
https://doi.org/10.1016/j.cell.2024.10.006
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Last Updated on November 4, 2024 by Marie Benz MD FAAD