Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy.
OBJECTIVE
Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization.


METHODS
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.
Departments of Dermatology, Pathology, Oncology, and jtaube1@jhmi.edu stopali1@jhmi.edu.
Janis M
JM
Taube
Pathology, Oncology, and Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; and.
Alison
A
Klein
Oncology, and.
Julie R
JR
Brahmer
Departments of Dermatology.
Haiying
H
Xu
Oncology, and.
Xiaoyu
X
Pan
Departments of Dermatology.
Jung H
JH
Kim
Department of Immunobiology, Yale University, New Haven, Connecticut.
Lieping
L
Chen
Oncology, and.
Drew M
DM
Pardoll
Surgery, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine; jtaube1@jhmi.edu stopali1@jhmi.edu.
Suzanne L
SL
Topalian
Pathology.
Robert A
RA
Anders
D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000378:metabolism*; D001706:Biopsy; D015870:Gene Expression; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000077594:Nivolumab; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab