90
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Epigenetic silencing of Th1 type chemokines shapes tumor immunity and immunotherapy

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism 1 However, its role in cancer immunopathology and immunotherapy is poorly understood. Using ovarian cancers as our model, we found that enhancer of zeste homolog 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase (DNMT) 1-mediated DNA methylation repress the tumor production of Th1-type chemokines CXCL9 and CXCL10, and subsequently determine effector T cell trafficking to the tumor microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T cell tumor infiltration, slows down tumor progression, and improves therapeutic efficacy of PD-L1 (B7-H1) checkpoint blockade 24 and adoptive T cell transfusion 5 in tumor bearing mice. Moreover, tumor EZH2 and DNMT1 are negatively associated with tumor infiltrating CD8 + T cells and patient outcome. Thus, epigenetic silencing of Th1-type chemokine is a novel tumor immune evasion mechanism. Selective epigenetic reprogramming alters T cell landscape 6 in cancer and may enhance clinical efficacy of cancer therapy.

          Related collections

          Most cited references19

          • Record: found
          • Abstract: found
          • Article: not found

          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Time-dependent ROC curves for censored survival data and a diagnostic marker.

            ROC curves are a popular method for displaying sensitivity and specificity of a continuous diagnostic marker, X, for a binary disease variable, D. However, many disease outcomes are time dependent, D(t), and ROC curves that vary as a function of time may be more appropriate. A common example of a time-dependent variable is vital status, where D(t) = 1 if a patient has died prior to time t and zero otherwise. We propose summarizing the discrimination potential of a marker X, measured at baseline (t = 0), by calculating ROC curves for cumulative disease or death incidence by time t, which we denote as ROC(t). A typical complexity with survival data is that observations may be censored. Two ROC curve estimators are proposed that can accommodate censored data. A simple estimator is based on using the Kaplan-Meier estimator for each possible subset X > c. However, this estimator does not guarantee the necessary condition that sensitivity and specificity are monotone in X. An alternative estimator that does guarantee monotonicity is based on a nearest neighbor estimator for the bivariate distribution function of (X, T), where T represents survival time (Akritas, M. J., 1994, Annals of Statistics 22, 1299-1327). We present an example where ROC(t) is used to compare a standard and a modified flow cytometry measurement for predicting survival after detection of breast cancer and an example where the ROC(t) curve displays the impact of modifying eligibility criteria for sample size and power in HIV prevention trials.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.

              Regulatory T (T(reg)) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen-reactive lymphocytes mediated by T(reg) cells; however, definitive evidence that T(reg) cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4(+)CD25(+)FOXP3(+) T(reg) cells in 104 individuals affected with ovarian carcinoma, that human tumor T(reg) cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor T(reg) cells are associated with a high death hazard and reduced survival. Human T(reg) cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of T(reg) cells to the tumor. This specific recruitment of T(reg) cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking T(reg) cell migration or function may help to defeat human cancer.
                Bookmark

                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                2 September 2015
                26 October 2015
                12 November 2015
                12 May 2016
                : 527
                : 7577
                : 249-253
                Affiliations
                [1 ]Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA, 48109
                [2 ]Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA, 48109
                [3 ]Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, MI, USA, 48109
                [4 ]Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA, 48109
                [5 ]The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Poland, 20-081
                [6 ]Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, MI, USA, 48109
                [7 ]The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA, 48109
                [8 ]Department of Women’s Health Services, Henry Ford Health System, Detroit, MI, USA, 48202
                [9 ]Graduate Program in Tumor Biology, University of Michigan, Ann Arbor, MI, USA, 48109
                Author notes
                [* ]Correspondence and requests for materials should be addressed to: Weiping Zou, M.D., Ph.D. at the Department of Surgery, University of Michigan School of Medicine, BSRB 5071, 109 Zina Pitcher Place, Ann Arbor, MI, 48109 or at wzou@ 123456med.umich.edu
                Article
                NIHMS718418
                10.1038/nature15520
                4779053
                26503055
                7ce7c959-58e1-4c80-849a-29719461ffc9

                Reprints and permissions information is available at www.nature.com/reprints.

                History
                Categories
                Article

                Uncategorized
                chemokine,cxcl9,cxcl10,trafficking,ezh2,dnmt,histone modification,dna methylation,epigenetics,chemotherapy,t cell therapy,pd-1,pd-l1,b7-h1,checkpoint,cancer

                Comments

                Comment on this article