Dongjun Peng

IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L.

Little is known about how the immune system impacts human colorectal cancer invasiveness and stemness. Here we detected interleukin-22 (IL-22) in patient colorectal cancer tissues that was produced predominantly by CD4(+) T cells. In a mouse model, migration of these cells into the colon cancer microenvironment required the chemokine receptor CCR6 and its ligand CCL20. IL-22 acted on cancer cells to promote activation of the transcription factor STAT3 and expression of the histone 3 lysine 79 (H3K79) methytransferase DOT1L. The DOT1L complex induced the core stem cell genes NANOG, SOX2, and Pou5F1, resulting in increased cancer stemness and tumorigenic potential. Furthermore, high DOT1L expression and H3K79me2 in colorectal cancer tissues was a predictor of poor patient survival. Thus, IL-22(+) cells promote colon cancer stemness via regulation of stemness genes that negatively affects patient outcome. Efforts to target this network might be a strategy in treating colorectal cancer patients.

PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer

Infiltration of tumors with effector T cells is positively associated with therapeutic efficacy and patient survival. However, the mechanisms underlying effector T-cell trafficking to the tumor microenvironment remain poorly understood in patients with colon cancer. The polycomb repressive complex 2 (PRC2) is involved in cancer progression, but the regulation of tumor immunity by epigenetic mechanisms has yet to be investigated. In this study, we examined the relationship between the repressive PRC2 machinery and effector T-cell trafficking. We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival. Collectively, our findings reveal that PRC2-mediated epigenetic silencing is not only a crucial oncogenic mechanism, but also a key circuit controlling tumor immunosuppression. Therefore, targeting epigenetic programs may have significant implications for improving the efficacy of current cancer immunotherapies relying on effective T-cell-mediated immunity at the tumor site.

Myeloid-Derived Suppressor Cells Endow Stem-like Qualities to Breast Cancer Cells through IL6/STAT3 and NO/NOTCH Cross-talk Signaling

Myeloid-derived suppressor cells (MDSC) contribute to immune suppression in cancer, but the mechanisms through which they drive metastatic progression are not fully understood. In this study, we show how MDSC convey stem-like qualities to breast cancer cells that coordinately help enable immune suppression and escape. We found that MDSC promoted tumor formation by enhancing breast cancer cell stem-like properties as well as by suppressing T-cell activation. Mechanistic investigations indicated that these effects relied upon cross-talk between the STAT3 and NOTCH pathways in cancer cells, with MDSC inducing IL6-dependent phosphorylation of STAT3 and activating NOTCH through nitric oxide leading to prolonged STAT3 activation. In clinical specimens of breast cancer, the presence of MDSC correlated with the presence of cancer stem-like cells (CSC) and independently predicted poor survival outcomes. Collectively, our work revealed an immune-associated mechanism that extrinsically confers cancer cell stemness properties and affects patient outcome. We suggest that targeting STAT3-NOTCH cross-talk between MDSC and CSC could offer a unique locus to improve cancer treatment, by coordinately targeting a coupled mechanism that enables cancer stemness and immune escape. Cancer Res; 76(11); 3156-65. ©2016 AACR.

Th22 cells control colon tumorigenesis through STAT3 and Polycomb Repression complex 2 signaling

ABSTRACT Th22 cells traffic to and retain in the colon cancer microenvironment, and target core stem cell genes and promote colon cancer stemness via STAT3 and H3K79me2 signaling pathway and contribute to colon carcinogenesis. However, whether Th22 cells affect colon cancer cell proliferation and apoptosis remains unknown. We studied the interaction between Th22 cells and colon cancer cells in the colon cancer microenvironment. Colon cancer proliferation was examined by flow cytometry analysis and H3 thymidine incorporation. Cell cycle related genes were quantified by real-time PCR and Western blotting. We transfected colon cancer cells with lentiviral vector encoding specific gene shRNAs and used chromatin immunoprecipitation (ChIP) assay to determine the genetic signaling involved in interleukin (IL)-22-mediated colon cancer cell proliferation. We showed that Th22 cells released IL-22 and stimulated colon cancer proliferation. Mechanistically, IL-22 activated STAT3, and subsequently STAT3 bound to the promoter areas of the Polycomb Repression complex 2 (PRC2) components SUZ12 and EED, and stimulated the expression of PRC2. Consequently, the activated PRC2 catalyzed the promoters of the cell cycle check-point genes p16 and p21, and inhibited their expression through H3K27me3-mediated histone methylation, and ultimately caused colon cancer cell proliferation. Bioinformatics analysis revealed that the levels of IL-22 expression positively correlated with the levels of genes controlling cancer proliferation and cell cycling in colon cancer. In addition to controlling colon cancer stemness, Th22 cells support colon carcinogenesis via affecting colon cancer cell proliferation through a distinct histone modification.