Overcoming resistance to anti-PD1 immunotherapy

摘要 新型癌症免疫疗法正在产生重大临床影响，特别是抗PD-1 单克隆抗体然而，解释为什么一部分患者对这些药物有反应的机制， 治疗，而其他患者并不完全理解。我们的初步数据 表明基线T细胞发炎肿瘤微环境可能是预测性生物标志物 对多种免疫疗法的反应。联合免疫疗法可能会推动临床 在这部分患者中的疗效。我们的过度假设是， 宿主中的多态性、肿瘤细胞的基因组特征以及肿瘤细胞的组成。 肠道微生物群深刻地影响自发性T细胞应答的程度 针对患者的肿瘤，这反过来将决定对 免疫疗法识别T细胞排斥的分子机制应该指向 新的治疗干预措施，将扩大对抗PD-1有反应的患者比例， 基于免疫疗法。虽然我们迄今为止的工作主要集中在黑色素瘤上，但最近的TCGA 分析表明，许多相同的原则适用于多种额外的癌症， 类型因此，拟议资助期的一个主要目标将是扩大我们的翻译能力， 研究策略涵盖接受抗PD-1治疗的所有癌症类型的患者， 基于免疫疗法。因此，预计这项工作的产出将产生深远的影响。 对癌症患者的总体结果的影响。

ABSTRACT Novel immunotherapies for cancer are having a major clinical impact, in particular anti-PD-1 mAbs. However, the mechanisms that explain why a subset of patients responds to these therapies while other patients do not remain incompletely understood. Our preliminary data suggest that a baseline T cell-inflamed tumor microenvironment may be a predictive biomarker for response to multiple immunotherapies. Combination immunotherapies may push clinical efficacy in this subset of patients further. Our over-arching hypothesis is that germline polymorphisms in the host, genomic features of the tumor cells, and the composition of intestinal microbiota profoundly influence the extent of a spontaneous T cell response against a patient's tumor, which in turn will determine the likelihood of response to immunotherapy. Identifying molecular mechanisms for T cell exclusion should point towards new therapeutic interventions that will expand the fraction of patients responding to anti-PD-1- based immunotherapies. While our work to date has focused on melanoma, recent TCGA analysis has indicated that many of the same principles apply to multiple additional cancer types. Thus, a major goal of the proposed funding period will be to broaden our translational research strategy to encompass patients with all cancer types being treated with anti-PD-1- based immunotherapies. The output of this work is therefore anticipated to have profound impact on cancer patient outcomes overall.