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Supplementary Figure S4 from Next-Generation Sequencing–Based MSI Scoring Predicts Benefit in Mismatch Repair–Deficient Tumors Treated with Nivolumab: Follow-up on NCI-MATCH Arm Z1D

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posted on 2025-02-17, 08:22 authored by Jonathan D. Schoenfeld, Nilofer S. Azad, Jacob Gross, Li Chen, Michael J. Overman, Katrina Kao, Latifa Jackson, Donna Brunnquell, Xiangning Bu, Christina Coppola, Ping Guan, Jennifer Lee, David Sims, Rebecca Fuchs, Jason L. Weirather, Kathleen L. Pfaff, Lauren Gunasti, Srin Ranasinghe, Stanley R. Hamilton, Victoria Wang, Peter J. O’Dwyer, Catherine J. Wu, Scott J. Rodig, David R. Patton, Lyndsay Harris

Mutations across genes by type and/or frequency

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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ARTICLE ABSTRACT

Mismatch repair–deficient (dMMR) tumors have demonstrated favorable responses to immune checkpoint inhibition targeting PD-1. However, more in-depth identification of predictors of response could further refine patient selection for immunotherapy treatment. We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI–Molecular Analysis for Therapy Choice arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with noncolorectal dMMR tumors. Genomic analyses were performed using next-generation sequencing (NGS), whole-exome sequencing, and RNA sequencing and supplemented by multiplex immunofluorescence performed on tissue samples. In this dMMR population, more extensive alterations of microsatellites as assessed by measures of NGS were associated with clinical benefit and tumor mutational burden. RNA sequencing further revealed associations between clinical benefit and immune infiltration index. Gene sets enriched in patients with clinical benefit included IFN signaling, antigen processing, and PI3K–AKT–mTOR signaling, whereas hedgehog signaling was found to be enriched in subjects lacking clinical benefit. These genomic data highlight the importance of immune infiltration and antigen presentation in dMMR tumors that respond to immune checkpoint blockade. In addition, they suggest that, even within a dMMR population, NGS-based measures of microsatellite instability could serve as biomarkers of immunotherapy response.

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    Clinical Cancer Research

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    BiomarkersPrognostic biomarkersImmunotherapyBiomarkers for immunotherapy

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