Role of Gut Microbiota in Modulating Immune Checkpoint Inhibitory Therapy for Cancer

免疫检查点抑制剂治疗（ICT）释放免疫系统，导致持续缓解， 到50%患有以前无法治愈的癌症的患者，如转移性黑色素瘤。但是宿主因素 人们对如何调节或支配信通技术反应知之甚少。最近的临床前数据表明， 微生物群是优化对信通技术的反应所必需的。这些肠道微生物群增强宿主 适应性免疫反应，特别是宿主免疫细胞，需要抗癌活性。我们最近 研究表明，对ICT有反应的成年黑色素瘤患者与对ICT有反应的成年黑色素瘤患者相比， 进行性疾病患者。在初步数据中，我们证明了精确的益生菌疗法（使用 我们在临床/转化研究中鉴定的特定细菌）增强了ICT在小鼠中的功效 而酸奶中常见的益生菌则不会。微生物群决定了PD-1的减少 在ICT后肠系膜淋巴结（MLN）中表达CD 4和CD 8 T细胞。值得注意的是，这些特定的肠道 微生物群具有更多数量的与人黑素瘤新抗原同源的蛋白质序列， 与无效的酸奶益生菌相比。此外，这些肠道微生物群诱导CD 4和CD 8 T细胞 IFN-γ和粒酶B的产生。有趣的是，肠道中没有引流淋巴结的小鼠 对ICT的回应。ICT促进肠道微生物群易位到MLN。最后，口服热杀 肠道微生物群并没有增强ICT的功效，这表明增强ICT需要活细菌。 因此，我们的中心假设是，只有既具有高免疫原性潜力又具有高免疫原性的肠道微生物群， 转移到腹腔引流淋巴结的能力将促进免疫细胞的活化/训练 从而提高ICT的效率。为了验证这一假设，我们将追求以下三个具体目标。第一、 我们将进一步确定对化疗有反应的黑色素瘤患者的肠道微生物组和肿瘤遗传差异， ICT与疾病进展的患者相比。其次，我们将确定环境和微生物因素 这决定了肠道微生物群转移到肠系膜淋巴结。第三，我们将阐明 肠道微生物群通过进行体外功能性免疫调节宿主免疫细胞抗肿瘤应答 免疫细胞测定以确定特定肠道微生物群是否以及如何引发免疫细胞， 识别肠道微生物群招募的特定免疫细胞。这些研究将奠定基础， 以下创新：1）肠道微生物群激活免疫防御癌症的新机制 和2）用于优化ICT在晚期癌症患者中的功效的新方法（精确益生菌）。

Immune checkpoint inhibitor therapy (ICT) unleashes the immune system resulting in durable remissions in up to 50% of patients with previously incurable cancers, such as metastatic melanoma. But the host factors that modulate or dictate ICT response are poorly understood. Recent, preclinical data suggests that specific gut microbiota are required for optimizing response to ICT. These commensal gut microbiota augment host adaptive immune responses, specifically host immune cells, needed for anti-cancer activity. We recently showed that adult melanoma patients who respond to ICT have a distinct gut microbiota signature compared to patients with progressive disease. In preliminary data, we demonstrated that precision probiotic therapy (using the specific bacteria that we identified in our clinical/translational study) augmented the efficacy of ICT in mice with melanoma whereas a probiotic commonly found in yogurt did not. Microbiota dictated a reduction in PD-1 expressing CD4 and CD8 T cells in mesenteric lymph nodes (MLNs) following ICT. Of note, these specific gut microbiota had a greater number of protein sequences homologous to human melanoma neoantigens when compared to the ineffective yogurt probiotic. Further, these gut microbiota induced CD4 and CD8 T cell production of IFN-gamma and Granzyme B. Interestingly, mice without draining lymph nodes in the gut did not respond to ICT. ICT promoted gut microbiota translocation into MLNs. Finally, oral administration of heat-killed gut microbiota did not augment ICT efficacy, suggesting that live bacteria are required for augmenting ICT. Therefore, our central hypothesis is that only gut microbiota that have both high immunogenic potential and the ability to translocate into the abdominal draining lymph nodes will facilitate activation/education of immune cells and thus augment ICT efficacy. To test this hypothesis, we will pursue the following three specific aims. First, we will further define both gut microbiome and tumor genetic differences in melanoma patients who respond to ICT compared to those with disease progression. Second, we will identify environmental and microbial factors that dictate gut microbiota translocation into mesenteric lymph nodes. Third, we will elucidate the mechanisms by which gut microbiota modulate host immune cell anti-tumor response by performing in vitro functional immune cell assays to determine if and how specific gut microbiota prime immune cells and in vivo studies to identify the specific immune cells recruited by gut microbiota. These studies will lay the groundwork for the following innovations: 1) a novel mechanism by which gut microbiota activate immune defenses against cancer and 2) a novel approach (precision probiotics) for optimizing ICT efficacy in advanced cancer patients.