Ridnour Lisa A, Cheng Robert Ys, Heinz William F, Pore Milind, Gonzalez Ana L, Femino Elise L, Moffat Rebecca L, Wink Adelaide L, Imtiaz Fatima, Coutinho Leandro L, Butcher Donna, Edmondson Elijah F, Rangel M Cristina, Wong Stephen Tc, Lipkowitz Stanley, Glynn Sharon A, Vitek Michael P, McVicar Daniel W, Li Xiaoxian, Anderson Stephen K, Paolocci Nazareno, Hewitt Stephen M, Ambs Stefan, Billiar Timothy R, Chang Jenny C, Lockett Stephen J, Wink David A
Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland, USA.
Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, and.
JCI Insight. 2025 Jul 15;10(16). doi: 10.1172/jci.insight.193091. eCollection 2025 Aug 22.
Tumor immunosuppression affects survival and treatment efficacy. Tumor NOS2/COX2 coexpression strongly predicts poor outcome in estrogen receptor-negative (ER-) breast cancer by promoting metastasis, drug resistance, cancer stemness, and immune suppression. Herein, a spatially distinct NOS2/COX2 and CD3+CD8+PD1- T effector (TEff) cell landscape correlated with poor survival in ER- tumors. NOS2 was primarily expressed at the tumor margin, whereas COX2 together with B7H4 was associated with immune desert regions lacking TEff cells, where a higher ratio of tumor NOS2 or COX2 to TEff cells predicted poor survival. Also, programmed cell death ligand 1/programmed cell death 1, regulatory T cells (TRegs), and IDO1 were primarily associated with stroma-restricted TEff cells. Regardless of the survival outcome, CD4+ T cells and macrophages were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to increased CD8+ TEff/CD4+ TReg ratio and CD8+ TEff infiltration while Nos2 deficiency had no significant effect, thus reinforcing our observations that COX2 is an essential component of immunosuppression through CD8+ TEff cell exclusion from the tumor. Our study indicates that tumor NOS2/COX2 expression plays a central role in tumor immune evasion, suggesting that strategies combining clinically available NOS2/COX2 inhibitors with immune therapy could provide effective options for the treatment of aggressive and drug-resistant ER- breast tumors.
肿瘤免疫抑制影响生存和治疗效果。肿瘤中一氧化氮合酶2（NOS2）/环氧化酶2（COX2）共表达通过促进转移、耐药性、癌症干性和免疫抑制，强烈预示雌激素受体阴性（ER-）乳腺癌的不良预后。在此，在ER-肿瘤中，空间上不同的NOS2/COX2和CD3 + CD8 + PD1 - T效应细胞格局与不良生存相关。NOS2主要在肿瘤边缘表达，而COX2与缺乏T效应细胞的免疫荒漠区域相关，其中肿瘤NOS2或COX2与T效应细胞的比例较高预示着不良生存。此外，程序性细胞死亡配体1/程序性细胞死亡1、调节性T细胞（Tregs）和吲哚胺2,3-双加氧酶1（IDO1）主要与基质限制的T效应细胞相关。无论生存结果如何，CD4 + T细胞和巨噬细胞主要存在于基质淋巴聚集物中。最后，在4T1模型中，COX2抑制导致CD8 + T效应细胞/ CD4 + Treg比例增加和CD8 + T效应细胞浸润增加，而Nos2缺乏没有显著影响，从而强化了我们的观察结果，即COX2是通过将CD8 + T效应细胞排除在肿瘤外而导致免疫抑制的重要组成部分。我们的研究表明，肿瘤NOS2/COX2表达在肿瘤免疫逃逸中起核心作用，这表明将临床可用的NOS2/COX2抑制剂与免疫疗法相结合的策略可为治疗侵袭性和耐药性ER-乳腺肿瘤提供有效的选择。
