Yan Cheng

Targeting of Tumoral NAC1 Mitigates Myeloid-Derived Suppressor Cell–Mediated Immunosuppression and Potentiates Anti–PD-1 Therapy in Ovarian Cancer

Abstract Epithelial ovarian cancer is the most common type of ovarian cancer with a low rate of response to immunotherapy such as immune checkpoint blockade therapy. In this study, we report that nucleus accumbens–associated protein 1 (NAC1), a putative driver of epithelial ovarian cancer, has a critical role in immune evasion. We showed in murine ovarian cancer models that depleting or inhibiting tumoral NAC1 reduced the recruitment and immunosuppressive function of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, led to significant increases of cytotoxic tumor-infiltrating CD8+ T cells, and promoted antitumor immunity and suppressed tumor progression. We further showed that tumoral NAC1 directly enhanced the transcription of CXCL16 by binding to CXCR6, thereby promoting MDSC recruitment to the tumor. Moreover, lipid C20:1T produced by NAC1-expressing tumor cells fueled oxidative metabolism of MDSCs and promoted their immune-suppressive function. We also showed that NIC3, a small-molecule inhibitor of NAC1, was able to sensitize mice bearing NAC1-expressing ovarian tumors to anti–PD-1 therapy. Our study reveals a critical role for NAC1 in controlling tumor infiltration of MDSCs and in modulating the efficacy of immune checkpoint blockade therapy. Thus, targeting of NAC1 may be exploited to sensitize ovarian cancer to immunotherapy.

PD-1 inhibitor plus concurrent chemoradiotherapy for high-risk locally advanced cervical cancer

Dual Inhibition of CDK12/CDK13 Targets Both Tumor and Immune Cells in Ovarian Cancer

Abstract Therapeutic perturbation of cyclin-dependent kinase 12 (CDK12) is proposed to have pleiotropic effects in ovarian cancer, including direct cytotoxicity against tumor cells and indirect induction of immunogenicity that confer synthetic sensitivity to immune-based treatment. However, formal testing of this hypothesis has been hindered by an insufficient mechanistic understanding of CDK12 and its close homolog CDK13, as well as generally unfavorable pharmacokinetics of available CDK12/CDK13 covalent inhibitors. In this study, we used an innovative arsenous warhead modality to develop an orally bioavailable CDK12/CDK13 covalent compound. The dual CDK12/CDK13 inhibitors ZSQ836 exerted potent anticancer activity in cell culture and mouse models and induced transcriptional reprogramming, including downregulation of DNA damage response genes. CDK12 and CDK13 were both ubiquitously expressed in primary and metastatic ovarian cancer, and the two kinases performed independent and synergistic functions to promote tumorigenicity. Unexpectedly, although ZSQ836 triggered genomic instability in malignant cells, it counterintuitively impaired lymphocytic infiltration in neoplastic lesions by interfering with T-cell proliferation and activation. These findings highlight the Janus-faced effects of dual CDK12/CDK13 inhibitors by simultaneously suppressing tumor and immune cells, offering valuable insights into the future direction of drug discovery to pharmacologically target CDK12. Significance: This study dissects the specific roles of CDK12 and CDK13 in ovarian cancer and develops a CDK12/CDK13 inhibitor that impairs both tumor and immune cells, which could guide future CDK12 inhibitor development.