Post-irradiation Intratumoral Heterogeneity Modulates Response to Immune Checkpoint Inhibition Therapy in a Murine Melanoma Model

Authors

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

Language

English

Publication Date

2-1-2023

Journal

Neoplasia

DOI

10.1016/j.neo.2022.100864

PMID

36571944

PMCID

PMC9800194

PubMedCentral® Posted Date

12-24-2022

PubMedCentral® Full Text Version

Post-print

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

Animals, Mice, Immune Checkpoint Inhibitors, Mice, Inbred C57BL, Melanoma, CTLA-4 Antigen, Adenocarcinoma, radiation therapy, immunotherapy, checkpoint inhibition, tumor mutational burden, intra-tumor heterogeneity, neoantigen, in situ vaccine

Published Open-Access

yes

Recommended Citation

Wang, Jie; Sud, Shivani; Qu, Yanli; et al., "Post-irradiation Intratumoral Heterogeneity Modulates Response to Immune Checkpoint Inhibition Therapy in a Murine Melanoma Model" (2023). Faculty, Staff and Student Publications. 792.
https://digitalcommons.library.tmc.edu/uthshis_docs/792