title: Epigenetic drugs as immunomodulators for combination therapies in solid tumors.
abstract: Continuously improving knowledge of the fine mechanisms regulating cross-talk between immune cells, and of their multi-faceted interactions with cancer cells, has prompted the development of several novel immunotherapeutic strategies for cancer treatment. Among these, modulation of the host's immune system by targeting immunological synapses has shown notable clinical efficacy in different tumor types. Despite this, objective clinical responses and, more importantly, long-term survival are achieved only by a fraction of patients; therefore, identification of the mechanism(s) responsible for the differential effectiveness of immune checkpoint blockade in specific patient populations is an area of intense investigation. Neoplastic cells can activate multiple mechanisms to escape from immune control; among these, epigenetic reprogramming is emerging as a key player. Selected tumor-associated antigens, Human Leukocyte Antigens, and accessory/co-stimulatory molecules required for efficient recognition of neoplastic cells by the immune system have been shown to be epigenetically silenced or down-regulated in cancer. Consistent with the inherent reversibility of epigenetic silencing, "epigenetic" drugs, such as inhibitors of DNA methyltransferases and of histone deacetylases, can restore the functional expression of these down-regulated molecules, thus improving the recognition of cancer cells by both the innate and adaptive immune responses. This review focuses on the immunomodulatory activity of epigenetic drugs and on their proposed clinical use in novel combined chemo-immunotherapeutic regimens for the treatment of solid tumors.
authors.affiliation: Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico Aviano, National Cancer Institute, Aviano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Sigalotti
authors.affiliation: Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico Aviano, National Cancer Institute, Aviano, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Fratta
authors.affiliation: Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Coral
authors.affiliation: Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. Electronic address: mmaiocro@gmail.com.
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D044127:Epigenesis, Genetic; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007167:Immunotherapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D017393:RNA Editing
chemical_list: D007155:Immunologic Factors
keywords: DNA methylation; Histone post-translational modifications; Immunostimulatory antibodies; Immunotherapy