CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1.

Details

Ressource 1Download: 22205715_Postprint.pdf (2788.91 [Ko])
State: Public
Version: author
Serval ID
serval:BIB_CC8800CC6D6F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1.
Journal
Cancer Research
Author(s)
Fourcade J., Sun Z., Pagliano O., Guillaume P., Luescher I.F., Sander C., Kirkwood J.M., Olive D., Kuchroo V., Zarour H.M.
ISSN
1538-7445 (Electronic)
ISSN-L
0008-5472
Publication state
Published
Issued date
2012
Volume
72
Number
4
Pages
887-896
Language
english
Abstract
Cytotoxic T cells that are present in tumors and capable of recognizing tumor epitopes are nevertheless generally impotent in eliciting tumor rejection. Thus, identifying the immune escape mechanisms responsible for inducing tumor-specific CD8(+) T-cell dysfunction may reveal effective strategies for immune therapy. The inhibitory receptors PD-1 and Tim-3 are known to negatively regulate CD8(+) T-cell responses directed against the well-characterized tumor antigen NY-ESO-1. Here, we report that the upregulation of the inhibitory molecule BTLA also plays a critical role in restricting NY-ESO-1-specific CD8(+) T-cell expansion and function in melanoma. BTLA-expressing PD-1(+)Tim-3(-) CD8(+) T cells represented the largest subset of NY-ESO-1-specific CD8(+) T cells in patients with melanoma. These cells were partially dysfunctional, producing less IFN-γ than BTLA(-) T cells but more IFN-γ, TNF, and interleukin-2 than the highly dysfunctional subset expressing all three receptors. Expression of BTLA did not increase with higher T-cell dysfunction or upon cognate antigen stimulation, as it does with PD-1, suggesting that BTLA upregulation occurs independently of functional exhaustion driven by high antigen load. Added with PD-1 and Tim-3 blockades, BTLA blockade enhanced the expansion, proliferation, and cytokine production of NY-ESO-1-specific CD8(+) T cells. Collectively, our findings indicate that targeting BTLA along with the PD-1 and Tim-3 pathways is critical to reverse an important mechanism of immune escape in patients with advanced melanoma.
Keywords
Antibodies, Blocking/pharmacology, Antigens, Neoplasm/immunology, Humans, Melanoma/immunology, Membrane Proteins, Programmed Cell Death 1 Receptor/antagonists & inhibitors, Programmed Cell Death 1 Receptor/metabolism, Receptors, Immunologic/antagonists & inhibitors, Receptors, Immunologic/metabolism, T-Lymphocytes, Cytotoxic/immunology, Tumor Microenvironment, Up-Regulation
Pubmed
Web of science
Open Access
Yes
Create date
19/03/2012 19:57
Last modification date
20/08/2019 16:47
Usage data