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

结肠癌免疫监视中回肠免疫反应的调节：DAMP、MAMP 和肠干细胞自身抗原

• 批准号: 431402787
• 负责人: Professorin Dr. Diana Dudziak
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/431402787?language=en
• 关键词: Regulation; ileal; immune; responses; immunosurveillance

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.

结肠癌（CC）代表了免疫学家的挑战难题。患有CC的患者的预后强烈依赖于包括T卵泡辅助细胞（TFH）的肿瘤浸润淋巴细胞，也依赖于化学疗法诱导的免疫血液。重要的是，尽管成功地应用于其他肿瘤类型（例如黑色素瘤），但阻止检查点抑制剂PD-1在缺乏微卫星不稳定性（MSINEG）的绝大多数CC中无效。因此，鉴定将耐受性与肠中免疫原性反应相关的调节途径将为开发CC成功的免疫肿瘤学方法铺平道路。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，表明卵巢凋亡 - 由化学治疗剂奥沙利铂诱导 - 触发这些反应中的IL-1β依赖性TFH和B细胞激活，这些反应与CC的有效免疫耐受性相关，并显示了对CC的有效免疫接种蛋白的潜在的氧化蛋白和PD-1-1-1-1-1。当回肠上皮细胞（IEC）无法经历CASP3/7依赖性凋亡时，IL-1β没有释放或存在耐受性微生物群，化学疗法就无法引起PD-1高的TFH反应来控制VIVO中CC生长的PD-1高。我们浏览了通过损伤和与微生物相关的分子模式激活的回肠抗原呈递细胞的不同亚集负责TFH和加密IEC特异性CD8+ T细胞反应的启动。因此，我们的双国联盟将解决三个目标：WP1将研究与免疫原性死亡有关的IEC内在因素（ICD）（鉴定自抗原，损伤相关的分子模式/炎性途径/炎症途径和抗原呈现细胞），WP2将集中在范围内的IEC上，同时链接元素的IEC（链接），同时链接元素（WP2），而WP2则链接（b3在结合奥沙利铂和抗PD-1抗体的前瞻性临床试验中，回肠免疫伴侣和微生物组指纹。这种伙伴关系将破译肠道耐受性和免疫学之间的边界，以成功地发展Misineg CC的PD1封锁。