title: Low doses of gamma irradiation potentially modifies immunosuppressive tumor microenvironment by retuning tumor-associated macrophages: lesson from insulinoma.
abstract: Tumor infiltrating iNOS+ macrophages under the influence of immunosuppressive tumor microenvironment gets polarized to tumor-promoting and immunosuppressive macrophages, known as tumor-associated macrophages (TAM). Their recruitment and increased density in the plethora of tumors has been associated with poor prognosis in cancer patients. Therefore, retuning of TAM to M1 phenotype would be a key for effective immunotherapy. Radiotherapy has been a potential non-invasive strategy to improve cancer immunotherapy and tumor immune rejection. Irradiation of late-stage tumor-bearing Rip1-Tag5 mice twice with 2 Gy dose resulted in profound changes in the inflammatory tumor micromilieu, characterized by induction of M1-associated effecter cytokines as well as reduction in protumorigenic and M2-associated effecter cytokines. Similarly, in vitro irradiation of macrophages with 2 Gy dose-induced expression of iNOS, NO, NFκBpp65, pSTAT3 and proinflammatory cytokines secretion while downregulating p38MAPK which are involved in iNOS translation and acquisition of an M1-like phenotype. Enhancement of various M2 effecter cytokines and angiogenic reprogramming in iNOs+ macrophage depleted tumors and their subsequent reduction by 2 Gy dose in Rip1-Tag5 transgenic mice furthermore demonstrated a critical role of peritumoral macrophages in the course of gamma irradiation mediated M1 retuning of insulinoma.
authors.affiliation: Translational Immunology Division , German Cancer Research Center (DKFZ) and National Center of Tumor Diseases (NCT) , Im-Neuenheimer Feld 460 , 69120 Heidelberg , Germany.
authors.forename: Hridayesh
authors.initials: H
authors.lastname: Prakash
authors.affiliation: Translational Immunology Division , German Cancer Research Center (DKFZ) and National Center of Tumor Diseases (NCT) , Im-Neuenheimer Feld 460 , 69120 Heidelberg , Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Klug
authors.affiliation: School of Life Sciences , University of Hyderabad , Hyderabad 500046 , India.
authors.forename: Vinod
authors.initials: V
authors.lastname: Nadella
authors.affiliation: School of Life Sciences , University of Hyderabad , Hyderabad 500046 , India.
authors.forename: Varadendra
authors.initials: V
authors.lastname: Mazumdar
authors.affiliation: Department of Visceral Surgery , University Medical Center , D-69120 Heidelberg , Germany and.
authors.forename: Hubertus
authors.initials: H
authors.lastname: Schmitz-Winnenthal
authors.affiliation: Translational Immunology Division , German Cancer Research Center (DKFZ) and National Center of Tumor Diseases (NCT) , Im-Neuenheimer Feld 460 , 69120 Heidelberg , Germany.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Umansky
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005720:Gamma Rays; D007108:Immune Tolerance; D007340:Insulinoma / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000528:radiation effects*; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000276:immunology*; D010641:Phenotype; D019139:Tumor Escape / Q000276:immunology / Q000528:radiation effects*; D059016:Tumor Microenvironment / Q000276:immunology / Q000528:radiation effects*
chemical_list: D016207:Cytokines