Regulation of ileal immune responses in the immunosurveillance of colon cancer:DAMPs, MAMPs, and intestinal stem cell self-antigens

结肠癌（CC）是免疫学家面临的一个具有挑战性的难题。患有CC的患者的预后强烈依赖于肿瘤浸润淋巴细胞，包括T滤泡辅助细胞（TFH），但也依赖于化疗诱导的免疫应答。重要的是，虽然成功地应用于其他肿瘤类型（例如黑色素瘤），但阻断检查点抑制剂PD-1在绝大多数缺乏微卫星不稳定性（MSIneg）的CC中无效。因此，鉴定将致耐受性与肠中免疫原性免疫应答解偶联的调节途径将为CC中成功的免疫肿瘤学方法的开发铺平道路。近年来，我们的德国-法国团队在小鼠和患者中提供了实验证据，表明在存在最小回肠微生物组的情况下，由化疗剂奥沙利铂诱导的回肠细胞凋亡触发IL-1β依赖性TFH和B细胞活化。这些反应与针对CC的有效免疫监视相关，并说明了奥沙利铂和PD-1阻断剂组合的潜力。当回肠上皮细胞（IEC）不能经历caspase 3/7依赖性凋亡时，没有IL-1β的释放或存在致耐受性微生物群，化疗不能引起PD-1高TFH应答，从而控制体内CC生长。我们推测，通过损伤和微生物相关分子模式激活的回肠抗原呈递细胞的不同亚群负责引发TFH和隐窝IEC特异性CD 8 + T细胞应答。 因此，我们的两国联合体将实现三个目标：WP 1将研究与免疫原性细胞死亡（ICD）相关的IEC内在因素（识别自身抗原、损伤相关分子模式/炎性体途径和抗原呈递细胞），WP 2将关注调节IEC的外在因素（微生物、TFH和B细胞应答之间的联系），而WP 3将在奥沙利铂和抗PD-1抗体组合的前瞻性临床试验中验证回肠免疫和微生物组指纹。这种合作关系将破译肠道耐受性和免疫力之间的边界，以成功开发MSIneg CC中的PD 1阻断。

Colon cancer (CC) represents a challenging conundrum for immunologists. The prognosis for patients suffering from CC strongly relies on tumor infiltrating lymphocytes including T follicular helper cells (TFH), but also chemotherapy-induced immune responses. Importantly, although successfully applied in other tumor types (e.g. melanoma), blocking the checkpoint-inhibitor PD-1 is not effective in the vast majority of CCs lacking microsatellite instability (MSIneg). Therefore, the identification of the regulatory pathways that uncouple the tolerogenic from the immunogenic immune responses in the intestine will pave the way for the development of successful immuno-oncological approaches in CC. In recent years, our German-French teams have provided experimental evidence in mice and patients that ileal apoptosis - induced by the chemotherapeutic agent oxaliplatin - triggers IL-1β-dependent TFH and B cell activation in the presence of a minimalistic ileal microbiome. These responses are associated with an effective immunosurveillance against CC and illustrate the potential of the combination of oxaliplatin and PD-1 blockade. When ileal epithelial cells (IEC) cannot undergo casp3/7-dependent apoptosis, there is no release of IL-1β or there is a tolerogenic microflora, chemotherapy fails to elicit PD-1high TFH responses that control CC growth in vivo. We surmise that distinct subsets of ileal antigen presenting cells activated through damage and microbe-associated molecular patterns are in charge of priming of TFH and crypt IEC-specific CD8+ T cell responses. Thus, our bi-national consortium will tackle three aims: WP1 will investigate the IEC intrinsic factors pertaining to immunogenic cell death (ICD) (identification of self-antigens, damage-associated molecular patterns/inflammasome pathway, and antigen presenting cells), WP2 will focus on extrinsic factors regulating IEC (links between microbes, TFH, and B cell responses), while WP3 will validate ileal immune and microbiome fingerprints in prospective clinical trials combining oxaliplatin and anti-PD-1 antibodies. This partnership will decipher the frontiers between gut tolerance and immunity for the successful development of PD1 blockade in MSIneg CC.