Sensitizing Immune-Refractory Ovarian Tumors via p53 Mutation-Tailored Immunotherapy

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.