title: Immune checkpoint inhibitors with radiotherapy and locoregional treatment: synergism and potential clinical implications.
abstract: OBJECTIVE
  Antigens recognized by T cells in tumors include differentiation antigens, overexpressed antigens, cancer-testis, and mutated tumor neoantigens. Ionizing radiation causes damage to multiple biomolecules by direct energy deposition or by generation of free radicals, leading to cell death when the damage cannot be repaired. Tumor cell death induced by radiation will generate specific molecular signals that are sensed by antigen-presenting cells and stimulate their maturation and ability to cross-present tumor-derived antigens to T cells. Immunogenic cell death will complement the activity of immune checkpoint inhibitors. We will provide the emerging information coming from preclinical and clinical testing about the combinations of immunotherapies and radiotherapy.
  
  
  RESULTS
  Radiation induces chemokines that attract effector T cells to the tumor and vascular adhesion molecules that facilitate T-cell infiltration. This process, which has been named 'immunogenic modulation', plays a role not only in regression of the irradiated tumor but also in amplifying and strengthening adaptive antitumor immunity. The ongoing process of killing of tumor cells by cytotoxic T lymphocytes sustains release of more tumor antigens and possibly promotes antigenic spread, that is, activation of a broader T-cell repertoire. Results of several ongoing clinical trials are testing the combination of radiotherapy with immune checkpoint inhibitor treatment. Data support a model whereby 'waves' of tumor cell killing by T cells primed by the initial radiation-elicited antigen release boost the immune response. This process can eventually achieve systemic tumor control.
  
  
  CONCLUSIONS
  Radiation therapy is confirmed to be a sensitizer of tumors to immune checkpoint inhibitors in clinical trials, and its application will be easy to implement and widespread. Conversely, many issues need to be addressed before radiotherapy can become such a valid immunogenic tool. An area of increasing importance will be the development of suitable biomarkers that will be able to reliably assess 'immunogenic tumor cell death', immune effector stimulation, and adaptive immunity. Such an immune profile of biomarkers will aid in searching for an optimal combination of radiotherapy and immunomodulation and allows patient selection and response prediction.
authors.affiliation: Istituto Europeo di Oncologia, Division of Experimental Cancer Medicine, Via Ripamonti 435, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Esposito
authors.forename: Carmen
authors.initials: C
authors.lastname: Criscitiello
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Curigliano
mesh_terms: D056704:Adaptive Immunity / Q000528:radiation effects; D000951:Antigens, Neoplasm / Q000276:immunology*; D016923:Cell Death / Q000276:immunology / Q000528:radiation effects; D003131:Combined Modality Therapy; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D009369:Neoplasms / Q000276:immunology / Q000534:rehabilitation / Q000628:therapy*; D011878:Radiotherapy / Q000379:methods*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm