BCAT2 Shapes a Noninflamed Tumor Microenvironment and Induces Resistance to Anti-PD-1/PD-L1 Immunotherapy by Negatively Regulating Proinflammatory Chemokines and Anticancer Immunity.
BCAT2 Shapes a Noninflamed Tumor Microenvironment and Induces Resistance to Anti-PD-1/PD-L1 Immunotherapy by Negatively Regulating Proinflammatory Chemokines and Anticancer Immunity.
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DOI：
10.1002/advs.202207155
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发表时间：
2023-03
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为了提高免疫检查点阻断（ICB）单药治疗的应答率，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，证实BCAT 2在膀胱癌中形成非炎症TME。多组学结果表明，BCAT 2通过抑制促炎细胞因子/趋化因子相关通路和T细胞趋化性通路的活性，对细胞毒性淋巴细胞募集具有抑制作用。免疫分析显示，CD 8 +T细胞相关趋化因子的分泌与BCAT 2保持稳健的负相关性，使BCAT 2+肿瘤细胞周围的CD 8 +T细胞从远到近呈下降趋势。BCAT 2缺陷和抗PD-1抗体的共治疗在体内具有协同效应，这意味着BCAT 2在联合治疗中的潜力。此外，BCAT 2在预测免疫治疗疗效方面的价值在多个免疫治疗队列中得到验证。总之，作为TME中的关键分子，BCAT 2是与ICB组合的新兴靶标和指导精确治疗的生物标志物。通过多组学分析、实验验证和队列比较，发现BCAT 2是免疫治疗中潜在的联合治疗靶点。抑制BCAT 2可以通过调节CD 8 +T细胞相关趋化因子的分泌水平，将非炎症肿瘤微环境（TME）转化为炎症TME。此外，它也是一种潜在的预测免疫治疗疗效的生物标志物。
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. By multiomics analysis, experiment validation and cohort comparison, it is found that BCAT2 is a potential combination therapy target in immunotherapy. Inhibition of BCAT2 can transform a noninflamed tumor microenvironment (TME) to an inflamed TME by regulating secretion levels of CD8+T‐cell‐related chemokines. Furthermore, it is also a potential predictive biomarker of efficacy of immunotherapy.
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