The Cross-talk Between Intestinal Microbiota and MDSCs Fuels Colitis-associated Cancer Development

Hadas Ashkenazi-Preiser, Or Reuven, Atara Uzan-Yulzari, Sharon Komisarov, Roy Cirkin, Sondra Turjeman, Carmel Even, Nira Twaik, Kerem Ben-Meir, Ivan Mikula, Leonor Cohen-Daniel, Yaron Meirow, Eli Pikarsky, Yoram Louzoun, Omry Koren, Michal Baniyash

Research output: Contribution to journalArticlepeer-review

Abstract

Intestinal chronic inflammation is associated with microbial dysbiosis and accumulation of various immune cells including myeloid-derived suppressor cells (MDSC), which profoundly impact the immune microenvironment, perturb homeostasis and increase the risk to develop colitis-associated colorectal cancer (CAC). However, the specific MDSCs-dysbiotic microbiota interactions and their collective impact on CAC development remain poorly understood. In this study, using a murine model of CAC, we demonstrate that CAC-bearing mice exhibit significantly elevated levels of highly immunosuppressive MDSCs, accompanied by microbiota alterations. Both MDSCs and bacteria that infiltrate the colon tissue and developing tumors can be found in close proximity, suggesting intricate MDSC-microbiota cross-talk within the tumor microenvironment. To investigate this phenomenon, we employed antibiotic treatment to disrupt MDSC-microbiota interactions. This intervention yielded a remarkable reduction in intestinal inflammation, decreased MDSC levels, and alleviated immunosuppression, all of which were associated with a significant reduction in tumor burden. Furthermore, we underscore the causative role of dysbiotic microbiota in the predisposition toward tumor development, highlighting their potential as biomarkers for predicting tumor load. We shed light on the intimate MDSCs-microbiota cross-talk, revealing how bacteria enhance MDSC suppressive features and activities, inhibit their differentiation into mature beneficial myeloid cells, and redirect some toward M2 macrophage phenotype. Collectively, this study uncovers the role of MDSC-bacteria cross-talk in impairing immune responses and promoting tumor growth, providing new insights into potential therapeutic strategies for CAC. SIGNIFICANCE: MDSCs-dysbiotic bacteria interactions in the intestine play a crucial role in intensifying immunosuppression within the CAC microenvironment, ultimately facilitating tumor growth, highlighting potential therapeutic targets for improving the treatment outcomes of CAC.

Original languageAmerican English
Pages (from-to)1063-1081
Number of pages19
JournalCancer research communications
Volume4
Issue number4
DOIs
StatePublished - 15 Apr 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors; Published by the American Association for Cancer Research.

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