Overcoming resistance to anti-PD1 immunotherapy

摘要 新的癌症免疫疗法正在产生重大的临床影响，特别是抗PD-1 单抗。然而，解释为什么一部分患者对这些疾病有反应的机制 治疗方法，而其他患者并不是完全了解。我们的初步数据 提示基线T细胞炎症的肿瘤微环境可能是一个可预测的生物标志物 对多种免疫疗法的反应。联合免疫疗法可能推动临床 在这一亚组患者中的疗效进一步。我们最重要的假设是生殖系 宿主的多态性、肿瘤细胞的基因组特征以及肿瘤细胞的组成 肠道微生物区系深刻影响自发性T细胞反应的程度 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- 以免疫疗法为基础。虽然我们到目前为止的工作主要集中在黑色素瘤上，但最近的TCGA 分析表明，许多相同的原理适用于多个额外的癌症 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 研究策略涵盖所有类型的癌症患者正在接受抗PD-1治疗- 以免疫疗法为基础。因此，这项工作的成果预计将具有深远的意义 对癌症患者整体预后的影响。

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.