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Personalized Medicine and Imaging

Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy

Janis M. Taube, Alison Klein, Julie R. Brahmer, Haiying Xu, Xiaoyu Pan, Jung H. Kim, Lieping Chen, Drew M. Pardoll, Suzanne L. Topalian and Robert A. Anders
Janis M. Taube
Departments of 1Dermatology,
2Pathology,
3Oncology, and
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  • For correspondence: jtaube1@jhmi.edu stopali1@jhmi.edu
Alison Klein
2Pathology,
3Oncology, and
5Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; and
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Julie R. Brahmer
3Oncology, and
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Haiying Xu
Departments of 1Dermatology,
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Xiaoyu Pan
3Oncology, and
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Jung H. Kim
Departments of 1Dermatology,
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Lieping Chen
6Department of Immunobiology, Yale University, New Haven, Connecticut
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Drew M. Pardoll
3Oncology, and
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Suzanne L. Topalian
4Surgery, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine;
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  • For correspondence: jtaube1@jhmi.edu stopali1@jhmi.edu
Robert A. Anders
2Pathology,
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DOI: 10.1158/1078-0432.CCR-13-3271 Published October 2014
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Abstract

Purpose: Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization.

Experimental Design: Patients (N = 41) with melanoma, non–small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti–PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens. Immunoarchitectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes.

Results: Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti–PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response.

Conclusions: Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti–PD-1 blockade. Clin Cancer Res; 20(19); 5064–74. ©2014 AACR.

See related commentary by Ribas and Tumeh, p. 4982

This article is featured in Highlights of This Issue, p. 4975

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received December 2, 2013.
  • Revision received March 27, 2014.
  • Accepted March 29, 2014.
  • ©2014 American Association for Cancer Research.

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Clinical Cancer Research: 20 (19)
October 2014
Volume 20, Issue 19
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Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy
Janis M. Taube, Alison Klein, Julie R. Brahmer, Haiying Xu, Xiaoyu Pan, Jung H. Kim, Lieping Chen, Drew M. Pardoll, Suzanne L. Topalian and Robert A. Anders
Clin Cancer Res October 1 2014 (20) (19) 5064-5074; DOI: 10.1158/1078-0432.CCR-13-3271

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Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy
Janis M. Taube, Alison Klein, Julie R. Brahmer, Haiying Xu, Xiaoyu Pan, Jung H. Kim, Lieping Chen, Drew M. Pardoll, Suzanne L. Topalian and Robert A. Anders
Clin Cancer Res October 1 2014 (20) (19) 5064-5074; DOI: 10.1158/1078-0432.CCR-13-3271
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