Collagen Fragments Produced in Cancer Mediate T Cell Suppression Through Leukocyte-Associated Immunoglobulin-Like Receptor 1.

Saskia V Vijver,Sol Langermann,Dallas Flies,Akashdip Singh,Eline T A M Mommers-Elshof,Ronald Copeland,M Inês Pascoal Ramos,Louis Boon,Jan Meeldijk,Linde Meyaard

doi:10.3389/fimmu.2021.733561

Abstract

The tumor microenvironment (TME) is a complex structure comprised of tumor, immune and stromal cells, vasculature, and extracellular matrix (ECM). During tumor development, ECM homeostasis is dysregulated. Collagen remodeling by matrix metalloproteinases (MMPs) generates specific collagen fragments, that can be detected in the circulation of cancer patients and correlate with poor disease outcome. Leukocyte-Associated Immunoglobulin-like Receptor-1 (LAIR-1) is an inhibitory collagen receptor expressed on immune cells in the TME and in the circulation. We hypothesized that in addition to ECM collagen, collagen fragments produced in cancer can mediate T cell immunosuppression through LAIR-1. Our analyses of TCGA datasets show that cancer patients with high tumor mRNA expression of MMPs, collagen I and LAIR-1 have worse overall survival. We show that in vitro generated MMP1 or MMP9 collagen I fragments bind to and trigger LAIR-1. Importantly, LAIR-1 triggering by collagen I fragments inhibits CD3 signaling and IFN-γ secretion in a T cell line. LAIR-2 is a soluble homologue of LAIR-1 with higher affinity for collagen and thereby acts as a decoy receptor. Fc fusion proteins of LAIR-2 have potential as cancer immunotherapeutic agents and are currently being tested in clinical trials. We demonstrate that collagen fragment-induced inhibition of T cell function could be reversed by LAIR-2 fusion proteins. Overall, we show that collagen fragments produced in cancer can mediate T cell suppression through LAIR-1, potentially contributing to systemic immune suppression. Blocking the interaction of LAIR-1 with collagen fragments could be an added benefit of LAIR-1-directed immunotherapy.

Highlights

The tumor microenvironment (TME) is immunosuppressive and can mediate resistance to therapies, including current immunotherapies [1]
When all TCGA cancer patients were stratified based on high or low tumoral mRNA expression of MMP1, MMP9, collagen I and LAIR-1 (Supplementary Figure 2), patients with MMPhighCOL1A1highLAIR1high tumors showed significantly worse overall survival compared to patients with MMPlowCOL1A1lowLAIR1low tumors (Figures 1A, B)
Density and stiffness correlate with worse prognosis of cancer patients [3], possibly because this provides a physical barrier for immune cells, limits drug diffusion, and could induce immunosuppression [4], all underscoring the important role of Collagen Fragments Inhibit T-Cell Function C

Summary

Introduction

The tumor microenvironment (TME) is immunosuppressive and can mediate resistance to therapies, including current immunotherapies [1]. The TME consists of different cell types such as tumor cells, cancer-associated fibroblasts (CAFs), and multiple types of immune cells - and the extracellular matrix (ECM) [2]. Changes in the ECM have been linked to poor prognosis in cancer patients [3]. These changes can be grouped into four remodeling processes. These include ECM deposition, which modifies the abundance and composition of ECM [4] and ECM post-translational modifications, altering the structural and biochemical characteristics of the ECM [5]. Force-mediated physical remodeling impacts ECM organization by increasing stiffness [8] and alignment of ECM fibers [9, 10]

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