Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma.

Autor:	Barsoumian HB; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Ramapriyan R; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Younes AI; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Caetano MS; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Menon H; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Comeaux NI; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Cushman TR; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Schoenhals JE; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Cadena AP; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Reilly TP; Bristol-Myers Squibb Co, New York, New York, USA., Chen D; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Masrorpour F; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Li A; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Hong DS; Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Diab A; Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Nguyen QN; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Glitza I; Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Ferrarotto R; Thoracic Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Chun SG; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Cortez MA; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Welsh J; Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA JWelsh@mdanderson.org.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2020 Oct; Vol. 8 (2).
DOI:	10.1136/jitc-2020-000537
Abstrakt:	Background: Despite some successes with checkpoint inhibitors for treating cancer, most patients remain refractory to treatment, possibly due to the inhibitory nature of the tumor stroma that impedes the function and entry of effector cells. We devised a new technique of combining immunotherapy with radiotherapy (XRT), more specifically low-dose XRT, to overcome the stroma and maximize systemic outcomes. Methods: We bilaterally established 344SQ lung adenocarcinoma tumors in 129Sv/Ev mice. Primary and secondary tumors were irradiated with either high-dose or low-dose of XRT with systemic anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte associated protein 4 administration. Survival and tumor growth were monitored for the various groups, and secondary tumors were phenotyped by flow cytometry for immune populations. Tumor growth factor-beta (TGF-β) cytokine levels were assessed locally after low-dose XRT, and specific immune-cell depletion experiments were conducted to identify the major contributors to the observed systemic antitumor effect. Results: Through our preclinical and clinical studies, we observed that when tumor burden was high, there was a necessity of combining high-dose XRT to 'prime' T cells at the primary tumor site, with low-dose XRT directed to secondary (metastatic) tumors to 'modulate the stroma'. Low-dose XRT improved the antitumor outcomes of checkpoint inhibitors by favoring M1 macrophage polarization, enhancing natural killer (NK) cell infiltration, and reducing TGF-β levels. Depletion of CD4 + T cells and NK cells abrogated the observed antitumor effect. Conclusion: Our data extend the benefits of low-dose XRT to reprogram the tumor environment and improve the infiltration and function of effector immune cells into secondary tumors. Competing Interests: Competing interests: JW serves on the science advisory boards for Alpine Immune Sciences, RefleXion Medical, Mavu Pharma, MolecularMatch and Checkmate Pharmaceuticals, and he is the founder of Healios Oncology, MolecularMatch, and OncoResponse companies. MD Anderson Cancer Center has a trademark for RadScopal (TM). JW has research support collaborations with Bristol Myers Squibb, Checkmate Pharmaceuticals, Mavu pharma, Merck, and Nanobiotix. AD is an advisory board member for Nektar Therapeutics. IG is a consultant for Bristol Myers Squibb and Array Biopharma. DSH has consulting/advisory role in Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics. DSH has research/grant funding from AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda. DSH's ownership interests include MolecularMatch (Advisor), OncoResponse (founder), Presagia Inc (Advisor). (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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