Abstract 644: Gut microbiota-derived metabolites as regulators of immunity in pre-cancer

Abstract

Abstract Introduction: Tryptophan (Trp) as an essential amino acid that can only be obtained through diet and is a precursor of serotonin and melatonin and required for protein and niacin biosynthesis. In addition, Trp is appreciated for its influence on both host and microbial metabolism. Trp is shunted into the Kyn pathway (mostly) and indolic pathway (bacterial degradation), especially in the immune cells. Both Kyn and Indole/indole derivatives, in part by activating the ligand-dependent transcription factor aryl hydrocarbon receptor (AHR), can become dysfunctional in cancer. Most individuals with cancer such as colon cancer, exhibit increased L-kynurenine levels, which in part is explained by progression of immunosuppressive phenotype and excessive inflammatory signaling molecules. To date, studies in mice and humans have linked Kyn and AHR as potent modulators of host immunity to colon cancer (CRC). Nothing is yet known about their role in pre-cancer, during the development of adenomatous polyps. We hypothesized that increases in plasma Kyn and I3A and their receptor AHR on immune cells would be detected in patients with pre-malignant polyps, suggesting dysbiosis and increased colon cancer risk due to immune modulation. Methods: We measured with mass spectrometry Kyn and I3A in plasma samples of 88 polyp patients and compared to 22 colon cancer patients. We analyzed by flow cytometry PBMCs from 64 newly diagnosed advanced polyp patients (40-70 years old) and 9 age-matched colon cancer patients in order to evaluate AHR expression in different subsets of T cells, NKT cells and NK cells, and their possible association with exhaustion markers Tim-3, LAG-3 and PD-1, as well as Granzyme K, and the presence of immunosuppressive Treg and MDSC. Results: We showed high level of expression of gut microbiota-derived metabolites in plasma of colon pre-cancer compared to cancer patients. We identified CD8+ T effector memory cells (TEM) as primary T cell population expressing their receptor AHR in polyp patients, which had a statistically significant association with Granzyme K expression, which is a hallmark of inflammaging. Conclusions: Our results suggest gut microbiota-derived metabolites as potential mediators of immunosuppression in the setting of premalignancy, which could increase cancer risk and be targets of cancer-preventing strategies. Citation Format: Amir Hossein Mohseni, Sedigheh Taghinezhad-S, Pamela L. Beatty, Olivera J. Finn. Gut microbiota-derived metabolites as regulators of immunity in pre-cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 644.