Abstract 3440: Local regulatory T cell dysfunction in gut mucosa post-infection prevents colorectal cancer establishment

Abstract Colorectal cancer (CRC) is among the most lethal intestinal diseases, claiming approximately 1 million lives globally each year, with an incidence rate of around 2 million cases annually, presenting a significant public health challenge. Investigations into the etiology of CRC and strategies to enhance patient survival have highlighted the role of infectious episodes in disrupting intestinal immune homeostasis. Our research indicates that the resolution of certain acute gastrointestinal infections, typically considered benign, leads to permanent remodeling of the immune and lymphatic systems in the gastrointestinal tract and adjacent organs, such as the mesentery and mesenteric lymph nodes. This remodeling results in chronic local inflammation, impairing specific regulatory responses in the intestinal mucosa. We have demonstrated that this chronic inflammatory environment increases susceptibility to inflammatory bowel diseases, prompting the hypothesis that a similar process could occur with CRC. To test this, we infected C57BL/6 mice with Yersinia pseudotuberculosis (YP) and, after bacterial clearance, we induced CRC by azoxymethane and dextran sodium sulfate treatment. On the contrary to our initial hypothesis, Mice previously infected with YP exhibited fewer countable tumors compared to naïve mice, suggesting that the prior infection might protect against cancer development. Concurrently, we observed that Treg lymphocytes in the colonic lamina propria of YP-infected mice are dysfunctional, as they fail to control inflammation in both the T cell transfer colitis model and in vitro suppression assays. We believe that Treg dysfunction post-YP infection may favor immune surveillance and support the reduction in tumor development, given that the tumor microenvironment typically recruits Tregs as an immune escape mechanism, and post-infection, these cells are unable to function correctly. Citation Format: Leonardo Mandu Gonçalves, Laura Barbosa da Conceição, Josiane Betim de Assis, Guilherme William da Silva, Gabriele Manamy Rodrigues, Bernardo de Castro Oliveira, Marcelo Valdemir de Araujo, Geovanni de Morais Lima, Adrian Martos Abreu, Clara Bueno Alves, Francielly Moreira, Marcos Paulo Coelho, Larissa Camargo da Silva, Eliane Aparecida Gomes Nascimento, Raissa Guimarães Ludwig, Marco Aurélio Ramirez Vinolo, Sandra Marcia Muxel, Erick Esteves de Oliveira, Ana Paula Lepique, Denise Morais da Fonseca. Local regulatory T cell dysfunction in gut mucosa post-infection prevents colorectal cancer establishment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3440.