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BCAT2 塑造非炎症肿瘤微环境,并通过负向调控促炎趋化因子和抗肿瘤免疫来诱导对抗 PD-1/PD-L1 免疫治疗的抵抗。

BCAT2 Shapes a Noninflamed Tumor Microenvironment and Induces Resistance to Anti-PD-1/PD-L1 Immunotherapy by Negatively Regulating Proinflammatory Chemokines and Anticancer Immunity.

机构信息

Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China.

National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China.

出版信息

Adv Sci (Weinh). 2023 Mar;10(8):e2207155. doi: 10.1002/advs.202207155. Epub 2023 Jan 15.

Abstract

To improve response rate of monotherapy of immune checkpoint blockade (ICB), it is necessary to find an emerging target in combination therapy. Through analyzing tumor microenvironment (TME)-related indicators, it is validated that BCAT2 shapes a noninflamed TME in bladder cancer. The outcomes of multiomics indicate that BCAT2 has an inhibitory effect on cytotoxic lymphocyte recruitment by restraining activities of proinflammatory cytokine/chemokine-related pathways and T-cell-chemotaxis pathway. Immunoassays reveal that secretion of CD8 T-cell-related chemokines keeps a robust negative correlation with BCAT2, generating a decreasing tendency of CD8 T cells around BCAT2 tumor cells from far to near. Cotreatment of BCAT2 deficiency and anti-PD-1 antibody has a synergistic effect in vivo, implying the potential of BCAT2 in combination therapy. Moreover, the value of BCAT2 in predicting efficacy of immunotherapy is validated in multiple immunotherapy cohorts. Together, as a key molecule in TME, BCAT2 is an emerging target in combination with ICB and a biomarker of guiding precision therapy.

摘要

为了提高免疫检查点阻断(ICB)单药治疗的反应率,有必要在联合治疗中寻找新的靶点。通过分析肿瘤微环境(TME)相关指标,验证了 BCAT2 在膀胱癌中形成了非炎症性的 TME。多组学的结果表明,BCAT2 通过抑制促炎细胞因子/趋化因子相关途径和 T 细胞趋化途径的活性,抑制细胞毒性淋巴细胞的募集。免疫分析显示,CD8 T 细胞相关趋化因子的分泌与 BCAT2 保持强烈的负相关,导致 CD8 T 细胞在 BCAT2 肿瘤细胞周围从远到近呈递减趋势。BCAT2 缺乏与抗 PD-1 抗体的联合治疗在体内具有协同作用,表明 BCAT2 在联合治疗中的潜力。此外,BCAT2 在多个免疫治疗队列中预测免疫治疗疗效的价值也得到了验证。总之,作为 TME 中的关键分子,BCAT2 是与 ICB 联合的新兴靶点,也是指导精准治疗的生物标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e271/10015882/584aad7c5cb9/ADVS-10-2207155-g008.jpg

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