Group 1 innate lymphocyte-derived IFN-γ regulates macrophage alternative activation in colon cancer

Abstract

Background Tumor-associated macrophage (TAM) is an important innate immune cell-subset in tumor microenvironment, and that is also a pivotal orchestrator of tumor-promoting inflammation and tumor progression. Evidence proved that TAMs are up-regulated in a great number of cancers, and most of them are alternative activated M2 phenotype, which greatly promote the progress of cancer diseases. Group 1 innate lymphocytes including conventional NK cells and type 1 innate lymphocytes (ILC1s), are abundant in intestinal tissue, and characterized by expressing transcription factor T-bet and secreting interferon (IFN)-γ, which can promote the macrophage to classically activated anti-tumor M1 phenotype. However, the relationship between these two cell subsets remains unclear in colon cancer. Methods Flow cytometry was used to detect the percentage of M1 phenotype macrophage, M2 phenotype macrophage and group 1 innate lymphocytes in colon cancer tissue and paracancer healthy colon tissue of AOM/DSS-induced colon cancer mice model. In vitroisolating group 1 innate lymphocytes and inducing bone marrow-derived macrophage to detect the cross-talk when co-cultured. Adoptively transfer or blocking group 1 innate lymphocytes in vivo to explore the role of group 1 innate lymphocytes on tumor-infiltrating macrophage and the tumor growth. Results We found that M1 phenotype macrophage and group 1 innate lymphocytes were down-regulated in colon cancer tissue, and they were positively correlated. Group 1 innate lymphocytes promoted macrophage to classically activated M1 phenotype in vitro, and that could be blocked by anti-IFN-γ. In vivo results showed that the administration of group 1 innate lymphocytes-blocking antibody anti-NK1.1 could decrease the number of M1 phenotype macrophages in tumor tissue of MC38 tumor-bearing mice and promote the tumor growth, while adoptively transferring group 1 innate lymphocytes led to tumor-inhibiting and level of M1 phenotype macrophage up-regulating in MC38 tumor-bearing mice. Conclusions Our studies preliminarily prove that group 1 innate lymphocytes promote the alternative activation of M1 macrophage by secreting IFN-γ and inhibit the progress of colon cancer for the first time, which may provide an insight in the immunotherapy of colon cancer.