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FIGURE 3 from The Cross-talk Between Intestinal Microbiota and MDSCs Fuels Colitis-associated Cancer Development

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posted on 2024-04-15, 14:20 authored by 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

CAC-associated microbiota promotes tumor development. A, Schematic presentation of CAC/FMT experiment and fecal sample collection. Created with BioRender.com. B, Weight change in CAC-induced mice during disease progression (n = 7–9). Weights are normalized to the starting point. C, Representative images of colons (left) and summarized tumor load (right). Black arrowheads represent macroscopic tumors. D, Representative H&E staining of colon sections. E, Spleen weights. Flow cytometry data showing the percentages of PMN-MDSCs (F) and M-MDSCs (G) in the spleens (n = 7–9). H, PCoA plots showing microbiota composition of control (n = 2) and CAC (n = 3) donor samples (pools) and fecal samples of recipient mice 14 days after microbiota transfer (T1). I, PCoA plots showing microbiota composition analysis of control and CAC-induced control-FMT and CAC-FMT mice at all timepoints (T1–T5) during the course of the experiment. Results are presented as mean ± SEM; *, P < 0.05; **, P < 0.01.

Funding

Israel Science Foundation (ISF)

Israel Cancer Research Fund (ICRF)

Ministry of Health, State of Israel (Ministry of Health)

Israel Ministry of Science and Technology

Bar-Ilan DSI funding

Gross Foundation (GROSS FOUNDATION INC)

Bruce and Baila Waldholtz funds

Joseph and Matilda Melnick Funds

History

ARTICLE 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. 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.