Abstract 4997: Auranofin enhances the efficacy of anti-PD1 immunotherapy

Abstract Anti-PD-1 immunotherapy brings hope for the treatment of malignant tumors, but its overall response rate is low. Therefore, how to sensitize anti-PD-1 therapy to make more patients benefit from immunotherapy is an urgent clinical demand. PKCι, a classical oncogene that affects cell proliferation and differentiation, has recently been found to be involved in the recruitment of immunosuppressive cells MDSCs and Tregs, which leads to anti-PD1 immunotherapy resistance. Our study is consistent with previously reported results that interfering with PKCι expression in tumor cells significantly enhances the anti-tumor effect of anti-PD1 therapy. Immunological mechanistic analyses demonstrated that the inhibition of PKCι expression significantly reduced the infiltration of tumor-associated macrophages (TAMs) rather than MDSCs or Tregs. Further studies revealed that PKCι enhanced the expression of macrophage chemokine CCL7 by promoting the formation of the YAP1/TEAD transcriptional complex. Interference in vitro and pharmacological inhibition of PKCι in tumor cells both significantly reduced CCL7 expression and TAMs invasion. Auranofin is a commonly used anti-inflammatory agent in clinical practice, which has been recently found that it directly induces tumor death by modulating the cellular redox system in tumor cells and remodels the tumor immunosuppressive microenvironment by specifically inhibiting PKCι expression. The results of our study showed that the anti-tumor effect of Auranofin combined with anti-PD1 therapy was superior to that of monotherapy in lung adenocarcinoma. Auranofin exerted synergistic anti-tumor effects with anti-PD1 immunotherapy by inhibiting the expression of PKCι-YAP1/TEAD-CCL7, reducing the recruitment of TAMs, and promoting the infiltration of effector CD8+ T cells. In summary, Auranofin is a potent candidate for sensitizing anti-PD-1 immunotherapy, reversing immunotherapy blunting by remodeling TIME, which provides new ideas and theoretical basis for immunotherapy of sensitizing malignant tumors. Citation Format: Zichen Zhao, Shichuan Hu, Yan Zhang. Auranofin enhances the efficacy of anti-PD1 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4997.