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

Javier Celis-Gutierrez,Peter Blattmann,Yunhao Zhai,Nicolas Jarmuzynski,Kilian Ruminski,Claude Grégoire,Youcef Ounoughene,Frédéric Fiore,Ruedi Aebersold,Romain Roncagalli,Matthias Gstaiger,Bernard Malissen

doi:10.1016/j.celrep.2019.05.041

Abstract

SummaryDeciphering 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.

Highlights

The T cell antigen receptor (TCR) occupies a central place in T cell activation, it does not work in isolation and is tuned by costimulatory and coinhibitory receptors that report on the immunogenic status of antigen-presenting cells (APCs)
The PD-1 Signalosome of Primary Effector CD4+ T Cells To identify the proteins that interact with PD-1 in primary effector T cells, we generated mice expressing a Twin-Strep-tag (OST) for affinity purification at the C terminus of endogenous PD-1 proteins (PD-1OST mice) (Figure 1A)
inhibition motif (ITIM) motifs (Watanabe et al, 2003), PD-1OST and WT CD4+ T cells showed a similar pattern of inducible tyrosine phosphorylation

Summary

Introduction

The T cell antigen receptor (TCR) occupies a central place in T cell activation, it does not work in isolation and is tuned by costimulatory and coinhibitory receptors that report on the immunogenic status of antigen-presenting cells (APCs). Proper integration of TCR, costimulatory, and coinhibitory signals is essential for peripheral tolerance induction and the generation of effector and memory T cells. During the effector phase of T cell responses, coinhibitory signals prevent overt tissue disruption. A systems-level understanding of the composition and dynamics of the signaling complexes (signalosomes) used by most T cell costimulators and coinhibitors under physiological conditions. Tumor-infiltrating effector T cells (TILs) often upregulate several coinhibitors that altogether dampen TCR and costimulatory signals. The reinvigorated anti-tumor immunity resulting from the coincident blockade of the programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) has triggered much interest in combination therapies (Sharpe and Pauken, 2018). There is an unmet need for the design of combination therapy trials that are informed by an understanding of the signaling pathways used by candidate coinhibitor pairs

Results

Discussion

Conclusion