Sensitizing Immune-Refractory Ovarian Tumors via p53 Mutation-Tailored Immunotherapy
Year: 2025
Type: preprint
Abstract: High-grade serous ovarian cancer demonstrates limited responsiveness to immune checkpoint inhibitors, owing in part to immunosuppressive environments shaped by nearly universal p53 aberrations. Utilizing an immunocompetent mouse model and individual p53 mutations, we identified a dependence of the p53-R270H mutation (equivalent of human R273H) on regulatory T cells (Tregs) and the PD-1/PD-L1 axis. Analysis of patient datasets associated R273H with elevated levels of two p53 targets, PD-L1 and amphiregulin (AREG), a Tregs growth factor. In contrast to p53-R172H tumors, where there was limited activity, dual antibody therapy targeting AREG and PD-L1 selectively and effectively inhibited R270H tumors. This involved polarization toward M1 macrophages, infiltration of CD8+ T cells, diminished Ly6G+ neutrophils and downregulation of interleukin-4. In patient-derived R273C organoids, the combination treatment reduced the CD4/CD8 ratio. This study is the first to establish a mutation-tailored therapeutic approach that leverages the capacity of p53 to modulate immunosuppressive mechanisms.
Authors: Rishita Chatterjee, Arturo Simoni-Nieves, An Truong, Moshit Lindzen, Furkan Ozmen, Christopher Cherry, Pascale Zwicky, Saptaparna Mukherjee, Boobash-Raj Selvadurai, Tomer-Meir Salame, Nitin Gupta, Suvendu Giri, Lior Kramarski, Yahel Avraham, Eviatar Weizman, Tugba Ozmen, Ashish Noronha, Priyasmita Chakrabarti, Deepthi Ramesh-Kumar, Julian Downward, Rony Dahan, Ido Amit, Victor Velculescu, James Brenton, Gordon Mills, Moshe Oren, Yosef Yarden
Institutions: Weizmann Institute of Science, University of Cambridge, Cancer Research UK, Oregon Health & Science University, OHSU Knight Cancer Institute, Johns Hopkins University, The Francis Crick Institute, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4411715708