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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• High-grade serous ovarian cancer (HGSOC) exhibits poor response to immune checkpoint inhibitors (ICIs).
• This limited efficacy is partly due to immunosuppressive tumor microenvironments driven by p53 mutations.
• p53 aberrations are nearly universal in HGSOC, highlighting their critical role.

Purpose of the Study:

• To investigate the role of specific p53 mutations in shaping the tumor immune microenvironment in HGSOC.
• To identify potential therapeutic strategies tailored to distinct p53 mutation profiles.
• To evaluate the efficacy of targeting regulatory T cells (Tregs) and the PD-1/PD-L1 axis in a mutation-specific manner.

Main Methods:

• Utilized an immunocompetent mouse model with specific p53 mutations (p53-R270H and p53-R172H).
• Analyzed patient datasets to correlate p53 mutations with immune markers (PD-L1, amphiregulin).
• Administered dual antibody therapy targeting amphiregulin (AREG) and PD-L1 in mouse models and patient-derived organoids.

Main Results:

• The p53-R270H mutation (human R273H equivalent) showed dependence on Tregs and the PD-1/PD-L1 axis.
• Elevated PD-L1 and AREG levels were associated with the R273H mutation in patients.
• Dual antibody therapy targeting AREG and PD-L1 selectively inhibited R270H tumors, leading to M1 macrophage polarization, CD8+ T cell infiltration, and reduced neutrophils.
• Combination treatment reduced the CD4/CD8 ratio in patient-derived R273C organoids.

Conclusions:

• Established a mutation-tailored therapeutic approach for HGSOC.
• Demonstrated that targeting AREG and PD-L1 is effective against p53-R273H mutant tumors.
• Leveraged p53's role in modulating immunosuppressive mechanisms for targeted cancer therapy.