title: ATM-mediated DNA damage signals mediate immune escape through integrin-αvβ3-dependent mechanisms.
abstract: Although the tumor microenvironment plays a critical role in tumor progression and metastasis, the relationship between chemotherapy resistance and modulation of the tumor microenvironment remains unclear. Here, we report a novel mechanism showing how constitutive DNA damage signals in therapy-resistant tumor cells suppress antitumor immunity in an integrin-αvβ3-dependent manner. Integrin-αvβ3 was upregulated on various therapy-resistant tumor cells through chronic activation of ATM/Chk2-and NFκB-mediated pathways. Inhibiting tumor-specific expression of integrin-αvβ3 improved therapeutic responses to anticancer drugs by stimulating endogenous host immune systems. Mechanistic investigations revealed that tumor-specific integrin-αvβ3 expression targeted dendritic cells, facilitating their ability to phagocytose viable therapy-resistant tumor cells and thereby impaired their ability to cross-prime antigen-specific T lymphocytes. Together, our results clarify the detrimental effects of constitutive DNA damage signals to chemosensitivity and antitumor immunity. Furthermore, these findings suggest that integrin-αvβ3 targeting may benefit patients' refractory to current anticancer regimens by defeating DNA damage signaling-induced immune escape.
authors.affiliation: Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Tokyo, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Jinushi
authors.forename: Shigeki
authors.initials: S
authors.lastname: Chiba
authors.forename: Muhammad
authors.initials: M
authors.lastname: Baghdadi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kinoshita
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Dosaka-Akita
authors.forename: Koyu
authors.initials: K
authors.lastname: Ito
authors.forename: Hironori
authors.initials: H
authors.lastname: Yoshiyama
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
authors.forename: Akinori
authors.initials: A
authors.lastname: Takaoka
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction; D019139:Tumor Escape; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D039302:Integrin alphaVbeta3; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases