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PMID: 22461641 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape.

Science translational medicine ·Vol. 4 ·No. 127 ·2012-03-28 ·Pages 127ra37

Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L

Abstract

Although many human cancers such as melanoma express tumor antigens recognized by T cells, host immune responses often fail to control tumor growth for as yet unexplained reasons. Here, we found a strong association between melanocyte expression of B7-H1 (PD-L1), an immune-inhibitory molecule, and the presence of tumor-infiltrating lymphocytes (TILs) in human melanocytic lesions: 98% of B7-H1(+) tumors were associated with TILs compared with only 28% of B7-H1(-) tumors. Indeed, B7-H1(+) melanocytes were almost always localized immediately adjacent to TILs. B7-H1/TIL colocalization was identified not only in melanomas but also in inflamed benign nevi, indicating that B7-H1 expression may represent a host response to tissue inflammation. Interferon-γ, a primary inducer of B7-H1 expression, was detected at the interface of B7-H1(+) tumors and TILs, whereas none was found in B7-H1(-) tumors. Therefore, TILs may actually trigger their own inhibition by secreting cytokines that drive tumor B7-H1 expression. Consistent with this hypothesis, overall survival of patients with B7-H1(+) metastatic melanoma was significantly prolonged compared with that of patients with B7-H1(-) metastatic melanoma. Therefore, induction of the B7-H1/PD-1 pathway may represent an adaptive immune resistance mechanism exerted by tumor cells in response to endogenous antitumor activity and may explain how melanomas escape immune destruction despite endogenous antitumor immune responses. These observations suggest that therapies that block this pathway may benefit patients with B7-H1(+) tumors.

MeSH Terms
Adaptive Immunity/immunology Adolescent Adult Aged Aged, 80 and over B7-H1 Antigen/genetics,metabolism Child Demography Female Follow-Up Studies Gene Expression Regulation, Neoplastic Humans Inflammation/complications,immunology,pathology Interferon-gamma/immunology Laser Capture Microdissection Lymphocytes, Tumor-Infiltrating/immunology,pathology Male Melanocytes/immunology,pathology Melanoma/complications,genetics,immunology,pathology Middle Aged Neoplasm Staging Reverse Transcriptase Polymerase Chain Reaction Skin Neoplasms/complications,genetics,immunology,pathology Survival Analysis Tumor Escape/immunology Young Adult
Chemicals
B7-H1 Antigen CD274 protein, human Interferon-gamma
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Taube Janis M
Department of Dermatology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA. jtaube1@jhmi.edu
Anders Robert A
Young Geoffrey D
Xu Haiying
Sharma Rajni
McMiller Tracee L
Chen Shuming
Klein Alison P
Pardoll Drew M
Topalian Suzanne L
Chen Lieping
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Article Info
Journal
Science translational medicine
Abbr.
Sci Transl Med
ISSN
1946-6242
DOI
10.1126/scitranslmed.3003689
Email
jtaube1@jhmi.edu
Published
2012-03-28
Pages
127ra37
Language
English
Region
United States
NLM ID
101505086
PMCID
PMC3568523
Subset
IM
Grants
NCI NIH HHS · CA97085 · United States
NIDDK NIH HHS · R01 DK080736 · United States
NIDDK NIH HHS · R01DK080736 · United States
NCI NIH HHS · CA85721 · United States
NIDDK NIH HHS · R01DK081417 · United States
NIDDK NIH HHS · R01 DK081417 · United States
NCI NIH HHS · CA016359 · United States
NCI NIH HHS · R01 CA142779 · United States
NCI NIH HHS · R01 CA163594 · United States
NCI NIH HHS · R01 CA085721 · United States
NCI NIH HHS · P30 CA006973 · United States
NCI NIH HHS · R01 CA097085 · United States
NCI NIH HHS · P30 CA016359 · United States
External Links
PubMed source DOI: 10.1126/scitranslmed.3003689 PMC Full Text View journal details
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