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）对免疫学家来说是一个具有挑战性的难题。CC患者的预后很大程度上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反应。重要的是，尽管成功地应用于其他肿瘤类型（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中并不有效。因此，在肠道中发现将耐受原性免疫反应与免疫原性免疫反应分离的调控途径，将为CC中成功的免疫肿瘤学方法的发展铺平道路。我们的德国和法国团队在小鼠和患者身上提供了实验证据，证明化疗药物奥沙利铂诱导的回肠细胞凋亡在极简的回肠微生物组存在下触发il -1β依赖性TFH和B细胞活化。这些反应与针对CC的有效免疫监视有关，并说明奥沙利铂和PD-1阻断联合使用的潜力。当回肠上皮细胞（IEC）不能经历casp3/7依赖性的凋亡，没有IL-1β的释放或存在耐受菌群时，化疗不能引起体内控制CC生长的pd -1高TFH反应。我们推测，通过损伤和微生物相关分子模式激活的不同的回肠抗原提呈细胞亚群负责启动TFH和隐窝iec特异性CD8+ T细胞反应。因此，我们的双边联盟将实现三个目标：WP1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/炎性体途径和抗原提呈细胞），WP2将重点研究调节IEC的外在因素（微生物、TFH和B细胞反应之间的联系），而WP3将在联合奥沙利铂和抗pd -1抗体的前瞻性临床试验中验证回肠免疫和微生物组指纹图谱。这一合作伙伴关系将破译肠道耐受性和免疫之间的前沿，从而成功开发mmsineg CC中的PD1阻断物。