Chronic inflammation promotes tumor growth and predisposes to metastasis. Microbes both induce inflammation and promote and associate with metastasis in cancer. Using faithful models of colorectal cancer (CRC) metastasis and autochthonous models of intestinal transformation we found that microbial translocation is essential for both primary tumor growth and metastasis.
Microbial components induced expression of two pro-tumorigenic cytokines Interleukin (IL)-17 and IL-27 whose expression level correlates with poor prognosis at different stages of CRC. Mechanistically, these microbiota-induced cytokines operated in different cell compartments.
IL-17 modified tumor microenvironment by acting on normal hepatocytes as a part of “seed and soil” metastasis paradigm and on tumor-infiltrating myeloid cells, leading to the suppression of innate and adaptive immunity and enhanced metastatic outgrowth. IL17 driven transcriptional program included modulation of metabolism as well as secretion of chemokines and pro-metastatic factors Pro-tumorigenic function of IL-27 was attributed to its ability to regulate cytotoxicity and exhaustion of tumor infiltrating CD8 T cells in cell autonomous and indirect way via T regulatory cells. Cell type specific ablation or neutralization of signaling by these cytokines led to a reduction in CRC metastasis and stimulation of anti-cancer immunity.
About the speaker
Sergei Grivennikov trained at National Cancer Institute/National Institutes of Health and University of California, San Diego, before joining Fox Chase Cancer Center in Philadelphia in 2012 and establishing his Lab at Cedars-Sinai Medical Center in Los Angeles in 2020.
His lab research interests are within the interconnection of studies in immune mechanisms, microbiota, tissue microenvironment and cancer using various animal models, organoids and an array of modern technologies. His lab decodes new inflammatory and immune mechanisms governing tumor microenvironment, tumor promotion and resistance to therapies, tissue regeneration and homeostasis. His recent work deals with cell type specific roles of IL17 and IL27 cytokine signaling in regulation of tumor microenvironment for colorectal cancer progression and metastasis. Microbiota-induced cytokine signaling exerts directly tumor promoting role on cancer cells and also regulates immunosuppression in innate lymphoid and T cells to accelerate metastasis.
