Targeting of tumoral NAC1 mitigates myeloid-derived suppressor cell-mediated immunosuppression and potentiates anti-PD-1 therapy in ovarian cancer.

Autor: Dong S; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University; Jiangsu, China, suzhou, China., Ye C; Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China, China., Li B; Department of Hepatopancreatobiliary Surgery, Suzhou Ninth Hospital Affiliated to Soochow University, Soochow University, Suzhou, Jiangsu, China, Suzhou, Jiangsu, China., Lv F; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University; Jiangsu, China;, Soochow, China., Zhang L; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University; Jiangsu, China;, Jiangsu, China;, China., Yang S; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University; Jiangsu, China;, Jiangsu, China;, China., Wang F; Department of Gynecology and obstetrics, First Affiliated Hospital, Soochow University, China, China., Zhu M; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University; Jiangsu, China;, suzhou, China., Zhou M; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University; Jiangsu, China;, Soochow, China., Guo F; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University; Jiangsu, China;, Soochow，Jiangsu, China;, China., Li Z; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University; Jiangsu, China;, Soochow, China., Peng L; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University; Jiangsu, China;, Soochow, China., Ji C; University of Southern California, Los Angeles, CA, United States., Lu X; Department of Pathology, Suzhou Ninth Hospital Affiliated to Soochow University, Soochow University, Suzhou, Jiangsu, China, China., Cheng Y; Center of Translational Medicine, First People's Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China, China., Ren X; University of Kentucky, College of Medicine, United States., Chen Y; First Affiliated Hospital of Soochow University, Suzhou, China., Zhou J; Department of Gynecology and obstetrics, First Affiliated Hospital, Soochow University, China, China., Yang J; University of Kentucky, Lexington, United States., Zhang Y; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University; Jiangsu, China, suzhou, China.
Jazyk: angličtina
Zdroj: Cancer immunology research [Cancer Immunol Res] 2024 Nov 12. Date of Electronic Publication: 2024 Nov 12.
DOI: 10.1158/2326-6066.CIR-24-0084
Abstrakt: Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer with a low rate of response to immunotherapy such as immune checkpoint blockade (ICB) therapy. Here, we report that nucleus accumbens-associated protein 1 (NAC1), a putative driver of EOC, 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 (MDSCs) in the tumor microenvironment (TME), 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 ICB therapy. Thus, targeting of NAC1 may be exploited to sensitize ovarian cancer to immunotherapy.
Databáze: MEDLINE
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