Format

Send to

Choose Destination
Cell Rep. 2019 Jun 11;27(11):3315-3330.e7. doi: 10.1016/j.celrep.2019.05.041.

Quantitative Interactomics in Primary T Cells Provides a Rationale for Concomitant PD-1 and BTLA Coinhibitor Blockade in Cancer Immunotherapy.

Author information

1
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France; Centre d'Immunophénomique, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France.
2
Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland.
3
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France.
4
Centre d'Immunophénomique, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France.
5
Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland; Faculty of Science, University of Zurich, 8006 Zurich, Switzerland.
6
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France. Electronic address: roncagalli@ciml.univ-mrs.fr.
7
Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland. Electronic address: matthias.gstaiger@imsb.biol.ethz.ch.
8
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France; Centre d'Immunophénomique, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France. Electronic address: bernardm@ciml.univ-mrs.fr.

Abstract

Deciphering how TCR signals are modulated by coinhibitory receptors is of fundamental and clinical interest. Using quantitative interactomics, we define the composition and dynamics of the PD-1 and BTLA coinhibitory signalosomes in primary effector T cells and at the T cell-antigen-presenting cell interface. We also solve the existing controversy regarding the role of the SHP-1 and SHP-2 protein-tyrosine phosphatases in mediating PD-1 coinhibition. PD-1 predominantly recruits SHP-2, but when absent, it recruits SHP-1 and remains functional. In contrast, BTLA predominantly recruits SHP-1 and to a lesser extent SHP-2. By separately analyzing the PD-1-SHP-1 and PD-1-SHP-2 complexes, we show that both dampen the TCR and CD28 signaling pathways equally. Therefore, our study illustrates how comparison of coinhibitory receptor signaling via quantitative interactomics in primary T cells unveils their extent of redundancy and provides a rationale for designing combinations of blocking antibodies in cancer immunotherapy on the basis of undisputed modes of action.

KEYWORDS:

BTLA; PD-1; SHP-1; SHP-2; T cell; cancer immunotherapy; coinhibitory receptors; combination therapy design; protein tyrosine phosphatases; quantitative interactomics

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center