Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade

Pei-Ling Chen(The University of Texas MD Anderson Cancer Center), Whijae Roh(The University of Texas MD Anderson Cancer Center), Alexandre Reuben(The University of Texas MD Anderson Cancer Center), Zachary A. Cooper(The University of Texas MD Anderson Cancer Center), Christine N. Spencer(The University of Texas MD Anderson Cancer Center), Peter A. Prieto(The University of Texas MD Anderson Cancer Center), John P. Miller(The University of Texas MD Anderson Cancer Center), Roland L. Bassett(The University of Texas MD Anderson Cancer Center), Vancheswaran Gopalakrishnan(The University of Texas MD Anderson Cancer Center), Khalida Wani(The University of Texas MD Anderson Cancer Center), Mariana Petaccia de Macêdo(The University of Texas MD Anderson Cancer Center), Jacob L. Austin-Breneman(The University of Texas MD Anderson Cancer Center), Hong Jiang(The University of Texas MD Anderson Cancer Center), Qing Chang(The University of Texas MD Anderson Cancer Center), Sangeetha M. Reddy(The University of Texas MD Anderson Cancer Center), Wei-Shen Chen(The University of Texas MD Anderson Cancer Center), Michael T. Tetzlaff(The University of Texas MD Anderson Cancer Center), Russell J. Broaddus(The University of Texas MD Anderson Cancer Center), Michael A. Davies(The University of Texas MD Anderson Cancer Center), Jeffrey E. Gershenwald(The University of Texas MD Anderson Cancer Center), Lauren E. Haydu(The University of Texas MD Anderson Cancer Center), Alexander J. Lazar(The University of Texas MD Anderson Cancer Center), Sapna P. Patel(The University of Texas MD Anderson Cancer Center), Patrick Hwu(The University of Texas MD Anderson Cancer Center), Wen-Jen Hwu(The University of Texas MD Anderson Cancer Center), Adi Diab(The University of Texas MD Anderson Cancer Center), Isabella C. Glitza(The University of Texas MD Anderson Cancer Center), Scott E. Woodman(The University of Texas MD Anderson Cancer Center), Luis M. Vence(The University of Texas MD Anderson Cancer Center), Ignacio I. Wistuba(The University of Texas MD Anderson Cancer Center), Rodabe N. Amaria(The University of Texas MD Anderson Cancer Center), Lawrence N. Kwong(The University of Texas MD Anderson Cancer Center), Víctor G. Prieto(The University of Texas MD Anderson Cancer Center), R. Eric Davis(The University of Texas MD Anderson Cancer Center), Wencai Ma(The University of Texas MD Anderson Cancer Center), Willem W. Overwijk(The University of Texas MD Anderson Cancer Center), Arlene H. Sharpe(Harvard University), Jianhua Hu(The University of Texas MD Anderson Cancer Center), P. Andrew Futreal(The University of Texas MD Anderson Cancer Center), Jorge Blando(The University of Texas MD Anderson Cancer Center), Padmanee Sharma(The University of Texas MD Anderson Cancer Center), James P. Allison(The University of Texas MD Anderson Cancer Center), Lynda Chin(The University of Texas MD Anderson Cancer Center), Jennifer A. Wargo(The University of Texas MD Anderson Cancer Center)
Cancer Discovery
June 15, 2016
10.1158/2159-8290.cd-15-1545
Cited by 1,008Open Access
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Abstract

UNLABELLED: 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. 818This article is highlighted in the In This Issue feature, p. 803.

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