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

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2023-02, Vol.36, p.100864-100864, Article 100864
• Main Authors: Wang, Jie, Sud, Shivani, Qu, Yanli, Li, Liantao, Zhang, Jiajie, Marron, David, Knape, Nicole Michelle, Kim, Isaiah James, Wagner, Kyle Thomas, Zhang, Tian, Zhao, Yuxia, Guo, Genyan, Wang, Andrew Z.
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animals; checkpoint inhibition; CTLA-4 Antigen; Immune Checkpoint Inhibitors; immunotherapy; in situ vaccine; intra-tumor heterogeneity; Melanoma; Mice; Mice, Inbred C57BL; neoantigen; radiation therapy; tumor mutational burden
• ISSN: 1476-5586; 1476-5586
• DOI: 10.1016/j.neo.2022.100864

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. 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. 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. Post-irradiation ITH modulates ICI response in a murine melanoma model. Irradiation may offer a mechanism to widen the therapeutic window of ICI.