New Breakthrough In Immunotherapy for Ovarian Cancer!

In recent years, immune checkpoint blockade (ICB) therapy has achieved remarkable results in the treatment of various cancers, but its efficacy in ovarian cancer, especially ovarian clear cell carcinoma (OCCC), still faces many challenges. Ovarian clear cell carcinoma is a rare and poor prognosis subtype of ovarian cancer. It is highly resistant to platinum chemotherapy and traditional treatments are ineffective. The median overall survival of patients with ovarian clear cell carcinoma after progression of first-line treatment is only 10.9 months, and the response rate to a single PD-1/PD-L1 inhibitor is extremely low, only 5% to 15%. Therefore, exploring new treatment strategies and prognostic markers is crucial to improving the clinical outcomes of patients with ovarian clear cell carcinoma.

Recently, in a research report entitled "PPP2R1A mutations portend improved survival after cancer immunotherapy" published in the international journal Nature, scientists from the University of Texas MD Anderson Cancer Center and other institutions focused on the response of patients with ovarian clear cell carcinoma to immune checkpoint blockade therapy through research. Through in-depth analysis of a cohort of ovarian clear cell carcinoma patients receiving immune checkpoint blockade therapy, the researchers found that patients with tumors carrying PPP2R1A gene mutations showed significantly prolonged overall survival and progression-free survival. The PPP2R1A gene encodes a common scaffold subunit of the protein phosphatase 2A (PP2A) complex, and its mutations are common in ovarian clear cell carcinoma. The researchers further verified this finding in a cohort of patients treated with immune checkpoint blockade therapy for multiple cancer types, and revealed the unique immune characteristics of PPP2R1A mutant tumors in immunotherapy through translational analysis.

Figure 1. PPP2R1A mutations are associated with longer survival after ICB in OCCC. (Dai Y, et al., 2025)

The experimental subjects in the article were 34 patients with platinum-resistant ovarian clear cell carcinoma who received combined treatment with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies. Among these patients, 11 patients' tumors carried PPP2R1A mutations. The researchers collected the patients' clinical data and performed next-generation sequencing analysis on tumor biopsy samples. The experimental process includes RNA sequencing of patient tumor samples, immune cell infiltration analysis, and spatial multi-omics analysis. At the same time, the researchers also used in vitro cell models and in vivo animal models to construct PPP2R1A mutant cell lines through CRISPR gene editing technology, and evaluated the sensitivity of these cell lines to CAR-T cell therapy and immune checkpoint blockade therapy.

The results showed that PPP2R1A mutant tumor samples showed enhanced IFNγ signaling pathway activity before treatment, indicating the activation of adaptive immune response. After immune checkpoint blockade therapy, multiple signaling pathways related to immune response in these samples were further enhanced, including inflammatory response, complement pathway, etc. In addition, PPP2R1A mutant tumor samples showed higher proportions of tumor-infiltrating CD8+ T cells and activated natural killer (NK) cells, and increased T cell receptor (TCR) and B cell receptor (BCR) richness after treatment. Spatial multi-omics analysis further revealed the presence of tertiary lymphoid structures (TLS) in PPP2R1A mutant samples, which were associated with good response to immune checkpoint blockade therapy. In animal models, PPP2R1A mutant tumors showed higher sensitivity to immune checkpoint blockade therapy, and tumor volume and weight were significantly reduced.

Finally, the researchers emphasized the importance of PPP2R1A mutation as a potential biomarker for predicting response to immune checkpoint blockade therapy. PPP2R1A mutations are not only associated with a good prognosis for patients with ovarian clear cell carcinoma who receive immune checkpoint blockade therapy, but may also improve the therapeutic effect by enhancing immune activation in the tumor microenvironment. In addition, the researchers also proposed the possibility of enhancing the efficacy of immune checkpoint blockade therapy by inhibiting PP2A activity with drugs, providing a new direction for future treatment strategies. Although the study sample size is limited and there may be potential effects of other mutations on treatment response, these findings provide important references and new research directions for immune checkpoint blockade therapy and immunotherapy for other cancer types, and are expected to improve patients' clinical prognosis.

Reference

Dai Y, et al. PPP2R1A mutations portend improved survival after cancer immunotherapy. Nature, 2025: 1-10.