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Supplementary Figures 1 - 13 from Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade

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posted on 2023-04-03, 21:02 authored by Pei-Ling Chen, Whijae Roh, Alexandre Reuben, Zachary A. Cooper, Christine N. Spencer, Peter A. Prieto, John P. Miller, Roland L. Bassett, Vancheswaran Gopalakrishnan, Khalida Wani, Mariana Petaccia De Macedo, Jacob L. Austin-Breneman, Hong Jiang, Qing Chang, Sangeetha M. Reddy, Wei-Shen Chen, Michael T. Tetzlaff, Russell J. Broaddus, Michael A. Davies, Jeffrey E. Gershenwald, Lauren Haydu, Alexander J. Lazar, Sapna P. Patel, Patrick Hwu, Wen-Jen Hwu, Adi Diab, Isabella C. Glitza, Scott E. Woodman, Luis M. Vence, Ignacio I. Wistuba, Rodabe N. Amaria, Lawrence N. Kwong, Victor Prieto, R. Eric Davis, Wencai Ma, Willem W. Overwijk, Arlene H. Sharpe, Jianhua Hu, P. Andrew Futreal, Jorge Blando, Padmanee Sharma, James P. Allison, Lynda Chin, Jennifer A. Wargo

Supplementary Figure 1. Immune profiling of pre-treatment, on-treatment and progression CTLA-4 blockade samples by immunohistochemistry. Supplementary Figure 2. Myeloid cell profiling of pre-treatment, on-treatment and progression CTLA-4 blockade samples by immunohistochemistry. Supplementary Figure 3. Increased contact between CD8 T cells and CD68 myeloid cells in non-responding patients to anti-CTLA-4 and anti-PD-1 therapy at pre-treatment CTLA-4 blockade, pre-treatment PD-1 blockade, and on-treatment PD-1 blockade time points. Supplementary Figure 4. Immune profiling of pre anti-PD-1, on-treatment anti-PD-1 and progression anti-PD-1 samples by immunohistochemistry. Supplementary Figure 5. Longitudinal increase in CD8, PD-1, and PD-L1 expression in responders to anti-PD-1 therapy. Supplementary Figure 6. Relative increase in CD8 T cell infiltrate at tumor center in responders to anti-PD-1 on treatment. Supplementary Figure 7. Significant increase in immune infiltrate between responders and non-responders to PD-1 blockade in absence of prior anti-CTLA-4 therapy. Supplementary Figure 8. Immune profiling of myeloid cells atpre-treatment and on-treatment PD-1 blockade time pointsby immunohistochemistry. Supplementary Figure 9. Heatmap of 54 NanoString samples. Supplementary Figure 10. Gene-specific NanoString concordance with immune profiling by IHC in pre-treatment, on-treatment and progression CTLA-4 blockade samples. Supplementary Figure 11. Gene-specific NanoString concordance with immune profiling by IHC in pre-treatment, on-treatment and progression PD-1 blockade samples. Supplementary Figure 12. Prior CTLA-4 blockade is not required for PD-1 early on-treatment profile. Supplementary Figure 13. Hierarchical clustering of gene expression across 54 samples confirms lack of batch effect.

Funding

Melanoma Research Alliance

Kenedy Memorial Foundation

NIH

CPRIT

Conquer Cancer Foundation

Robert Welch Distinguished University

Merck, Novartis/Array, and Bristol-Myers Squibb

Bristol-Myers Squibb, Merck, GlaxoSmithKline, and MedImmune

MD Anderson

National Science Foundation

History

ARTICLE ABSTRACT

Immune checkpoint blockade represents a major breakthrough in cancer therapy; however, responses are not universal. Genomic and immune features in pretreatment tumor biopsies have been reported to correlate with response in patients with melanoma and other cancers, but robust biomarkers have not been identified. We studied a cohort of patients with metastatic melanoma initially treated with cytotoxic T-lymphocyte–associated antigen-4 (CTLA4) blockade (n = 53) followed by programmed death-1 (PD-1) blockade at progression (n = 46), and analyzed immune signatures in longitudinal tissue samples collected at multiple time points during therapy. In this study, we demonstrate that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade and also demonstrate differential effects on the tumor microenvironment induced by CTLA4 and PD-1 blockade. Importantly, potential mechanisms of therapeutic resistance to immune checkpoint blockade were also identified.Significance: These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine and should be explored in immune checkpoint blockade treatment across cancer types. Cancer Discov; 6(8); 827–37. ©2016 AACR.See related commentary by Teng et al., p. 818.This article is highlighted in the In This Issue feature, p. 803