Post-irradiation intratumoral heterogeneity modulates response to immune checkpoint inhibition therapy in a murine melanoma model.

Autor:	Wang J; Department of Radiation Oncology University of North Carolina-Chapel Hill, Chapel Hill, NC; Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning China, 110032; Department of Radiation Oncology, Dalian Municipal Central Hospital, Dalian, Liaoning China, 116033. Electronic address: wangjiezxyy@icloud.com., Sud S; Department of Radiation Oncology University of North Carolina-Chapel Hill, Chapel Hill, NC. Electronic address: shivani.sud@unchealth.unc.edu., Qu Y; Department of Thoracic Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China,110042. Electronic address: quyanli@cancerhosp-ln-cmu.com., Li L; Department of Radiation Oncology University of North Carolina-Chapel Hill, Chapel Hill, NC; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. Electronic address: liliantao@xzhmu.edu.cn., Zhang J; Department of Radiation Oncology University of North Carolina-Chapel Hill, Chapel Hill, NC; Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China, 200040. Electronic address: 16111220055@fudan.edu.cn., Marron D; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC. Electronic address: dmarron@cs.unc.edu., Knape NM; Department of Radiation Oncology University of North Carolina-Chapel Hill, Chapel Hill, NC. Electronic address: Nicole_Knape@med.unc.edu., Kim IJ; Department of Radiation Oncology University of North Carolina-Chapel Hill, Chapel Hill, NC. Electronic address: isaiah_kim@med.unc.edu., Wagner KT; Department of Radiation Oncology University of North Carolina-Chapel Hill, Chapel Hill, NC. Electronic address: kyle.t.wagner@outlook.com., Zhang T; Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, NC; Department of Medicine, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX. Electronic address: tian.zhang@utsouthwestern.edu., Zhao Y; Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning China, 110032. Electronic address: zhaoyx2019@hotmail.com., Guo G; Department of Radiation Oncology University of North Carolina-Chapel Hill, Chapel Hill, NC; Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning China, 110032. Electronic address: gyguo@cmu.edu.cn., Wang AZ; Department of Radiation Oncology University of North Carolina-Chapel Hill, Chapel Hill, NC; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX. Electronic address: andrew.wang2@utsouthwestern.edu.
Jazyk:	angličtina
Zdroj:	Neoplasia (New York, N.Y.) [Neoplasia] 2023 Feb; Vol. 36, pp. 100864. Date of Electronic Publication: 2022 Dec 24.
DOI:	10.1016/j.neo.2022.100864
Abstrakt:	Purpose: The underlying mechanism for radiation as a potentiator of immune checkpoint inhibition (ICI) is unclear. We developed a novel murine model to investigate the effects of post-irradiation intratumoral heterogeneity (ITH) on response to ICI. Experimental Design: Parental mouse melanoma B16F10 cells were irradiated in vitro (5Gy x 3 fractions), then an a priori determined number of resulting colonies were implanted in C57BL/6J immunocompetent mice creating syngeneic models of unirradiated (parental) and irradiated tumors with low (irradiated-L) and high (irradiated-H) ITH. Mice were treated with placebo, α-PD-L1, α-CTLA-4 or dual ICI. Murine tumors underwent whole exome sequencing (WES). Clinically correlated paired pre- and post-irradiation patient rectal adenocarcinoma samples underwent WES. Results: Irradiated-L tumors showed increased tumor mutational burden (TMB) and a sustained decrease in ITH. Irradiated-L tumors were predicted to express five neoantigens with high variant allele frequency/clonal distribution. Mice with irradiated-L and irradiated-H versus parental B16F10 tumors demonstrated longer overall survival with dual ICI. Only mice with irradiated-L tumors experienced an overall survival benefit with single agent ICI. Clinically correlated rectal adenocarcinoma samples showed similarly increased TMB and decreased ITH following irradiation. Conclusions: Post-irradiation ITH modulates ICI response in a murine melanoma model. Irradiation may offer a mechanism to widen the therapeutic window of ICI. Competing Interests: Declaration of Competing Interest The authors declare no relevant conflict of interest. Full disclosures are provided. TZ has received research funding to institution from Acerta Pharma, Astellas Pharma, Janssen, Merrimack, Merck, Mirati Therapeutics, Novartis, OmniSeq, Personal Genome Diagnostics, Pfizer, Regeneron, StemCentRx; consulting or advisory roles at Amgen, AstraZeneca, Bristol-Myers Squibb, Calithera Biosciences, Dendreon, Exelixis, Foundation Medicine, Genentech/Roche, Janssen, Pharmacyclics, Pfizer, Sanofi, SeaGen, and QED Therapeutics; Honoraria from Exelixis, Genentech/Roche, MJH Life Science, Pacific Genuity; speaker's bureau at Genomic Health and Sanofi/Aventis; stock and other ownership interests at Archimmune Therapeutics (immediate family member), Capio Biosciences (immediate family member), and Nanorobotics (immediate family member). AZW has received research funding from Varian and is a cofounder of Archimmune Therapeutics and Capio Sciences. He also serves on the scientific board of Nanorobotics. (Copyright © 2022. Published by Elsevier Inc.)
Databáze:	MEDLINE
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