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, 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. GershenwaldLauren 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

Research output: Contribution to journalArticle

282 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)827-837
Number of pages11
JournalCancer discovery
Volume6
Issue number8
DOIs
StatePublished - Aug 2016

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ASJC Scopus subject areas

  • Oncology

Cite this

Chen, P. L., Roh, W., Reuben, A., Cooper, Z. A., Spencer, C. N., Prieto, P. A., Miller, J. P., Bassett, R. L., Gopalakrishnan, V., Wani, K., De Macedo, M. P., Austin-Breneman, J. L., Jiang, H., Chang, Q., Reddy, S. M., Chen, W. S., Tetzlaff, M. T., Broaddus, R. J., Davies, M. A., ... Wargo, J. A. (2016). Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer discovery, 6(8), 827-837. https://doi.org/10.1158/2159-8290.CD-15-1545