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

• Applicant: Professorin Dr. Diana Dudziak
• Subject Area: Immunology ; Gastroenterology ; Pathology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431402787

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.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Professorin Dr. Laurence Zitvogel