title: Immune-Mediated and Hypoxia-Regulated Programs: Accomplices in Resistance to Anti-angiogenic Therapies.
abstract: In contrast to mechanisms taking place during resistance to chemotherapies or other targeted therapies, compensatory adaptation to angiogenesis blockade does not imply a mutational alteration of genes encoding drug targets or multidrug resistance mechanisms but instead involves intrinsic or acquired activation of compensatory angiogenic pathways. In this article we highlight hypoxia-regulated and immune-mediated mechanisms that converge in endothelial cell programs and preserve angiogenesis in settings of vascular endothelial growth factor (VEGF) blockade. These mechanisms involve mobilization of myeloid cell populations and activation of cytokine- and chemokine-driven circuits operating during intrinsic and acquired resistance to anti-angiogenic therapies. Particularly, we focus on findings underscoring a role for galectins and glycosylated ligands in promoting resistance to anti-VEGF therapies and discuss possible strategies to overcome or attenuate this compensatory pathway. Finally, we highlight emerging evidence demonstrating the interplay between immunosuppressive and pro-angiogenic programs in the tumor microenvironment (TME) and discuss emerging combinatorial anticancer strategies aimed at simultaneously potentiating antitumor immune responses and counteracting aberrant angiogenesis.
authors.affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428, Buenos Aires, Argentina. dcrocirusso@gmail.com.
authors.forename: Diego O
authors.initials: DO
authors.lastname: Croci
authors.affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428, Buenos Aires, Argentina.
authors.forename: Santiago P
authors.initials: SP
authors.lastname: Mendez-Huergo
authors.affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428, Buenos Aires, Argentina.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Cerliani
authors.affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428, Buenos Aires, Argentina. gabyrabi@gmail.com.|Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428, Buenos Aires, Argentina. gabyrabi@gmail.com.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
mesh_terms: D018925:Chemokines; D016207:Cytokines; D019008:Drug Resistance, Neoplasm; D037161:Galectins; D006801:Humans; D000860:Hypoxia; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D018925:Chemokines; D016207:Cytokines; D037161:Galectins; D042461:Vascular Endothelial Growth Factor A
keywords: Angiogenesis; Anti-angiogenic therapy; Galectins; Hypoxia; Immunotherapy; Resistance