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

Jie Wang; Shivani Sud; Yanli Qu; Liantao Li; Jiajie Zhang; David Marron; Nicole Michelle Knape; Isaiah James Kim; Kyle Thomas Wagner; Tian Zhang; Yuxia Zhao; Genyan Guo; Andrew Z Wang

doi:10.1016/j.neo.2022.100864

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

Neoplasia. 2023 Feb:36:100864. doi: 10.1016/j.neo.2022.100864. Epub 2022 Dec 24.

Authors

Jie Wang¹, Shivani Sud², Yanli Qu³, Liantao Li⁴, Jiajie Zhang⁵, David Marron⁶, Nicole Michelle Knape⁷, Isaiah James Kim⁸, Kyle Thomas Wagner⁹, Tian Zhang¹⁰, Yuxia Zhao¹¹, Genyan Guo¹², Andrew Z Wang¹³

Affiliations

¹ 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.
² Department of Radiation Oncology University of North Carolina-Chapel Hill, Chapel Hill, NC. Electronic address: shivani.sud@unchealth.unc.edu.
³ 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.
⁴ 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.
⁵ 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.
⁶ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC. Electronic address: dmarron@cs.unc.edu.
⁷ Department of Radiation Oncology University of North Carolina-Chapel Hill, Chapel Hill, NC. Electronic address: Nicole_Knape@med.unc.edu.
⁸ Department of Radiation Oncology University of North Carolina-Chapel Hill, Chapel Hill, NC. Electronic address: isaiah_kim@med.unc.edu.
⁹ Department of Radiation Oncology University of North Carolina-Chapel Hill, Chapel Hill, NC. Electronic address: kyle.t.wagner@outlook.com.
¹⁰ 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.
¹¹ Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning China, 110032. Electronic address: zhaoyx2019@hotmail.com.
¹² 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.
¹³ 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.

Abstract

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.

Keywords: checkpoint inhibition; immunotherapy; in situ vaccine; intra-tumor heterogeneity; neoantigen; radiation therapy; tumor mutational burden.

MeSH terms

Adenocarcinoma*
Animals
CTLA-4 Antigen
Immune Checkpoint Inhibitors
Melanoma*
Mice
Mice, Inbred C57BL

Substances

Immune Checkpoint Inhibitors
CTLA-4 Antigen