Abstract 4090: Gut microbiota mimics as a source of cross-reactive tumor rejection antigens

Abstract The crosstalk between gut microbiome and anti-tumor immunity has recently gained attention in clinical settings. The administration of antibiotics during immune checkpoint blockade (ICB) therapies has been correlated with poorer outcomes in cancer patients, suggesting that microbiome alterations affect overall responses to ICB. The establishment of microbiota-specific T cell clones with tumor cross-reactivity potential was proposed as one of the mechanisms linking the microbiome to anti-tumor responses. Vaccine-based strategies aimed at reactivating these dormant pools of T cells to help eliminate tumors have been proposed as an alternate approach, but the parameters required for successful responses remain poorly understood. Here, we performed in silico selection of bacterial peptides derived from healthy mice based on their mimicry of either tumor-associated antigens (TAAs) or neoantigens expressed by murine melanoma cells and not healthy tissue. We show that in silico predicted peptide binding affinity to MHC I correlates with experimental MHC I binding, a key factor associated with strong immune responses. Moreover, we confirmed that a significant proportion of selected peptide candidates can provoke an immune reaction in a vaccination setting. From this group of peptides, we selected candidates which triggered cross-reactive immune responses against TAAs or neoantigens. Data from preliminary tumor challenge experiments with prophylactic peptide vaccination and ICB allowed us to define key parameters such as target gene expression levels which can predict the cross-reactive potential of bacterial peptides that mimic tumor antigens. These findings provide novel insights into the design of gut microbiome peptide-based tumor vaccines and pave the way for establishing combinatorial therapies with immunomodulatory drugs. Citation Format: Vincent Panneton, Mathieu Gigoux, Abderezak Zebboudj, Norah Sadek, Hyejin Choi, Levi M. Mangarin, Mariam M. George, Guillaume Kulakowski, Joao G. Magalhaes, Jean-Marie Carpier, Thibaud Dugat, Camille Gaal, Francesco Strozzi, Lorenzo Tibaldi, Laurent Chene, Jedd D. Wolchok, Vinod P. Balachandran, Taha Merghoub. Gut microbiota mimics as a source of cross-reactive tumor rejection antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4090.