Cancer immunotherapy by NC410, a LAIR-2 Fc protein blocking human LAIR-collagen interaction.

M Ines Pascoal Ramos,Christina Jensen,Jason Bosiacki,Linda Liu,Zachary Cusumano,Dallas Flies,Linjie Tian,Saskia V Vijver,Akashdip Singh,Ana Paucarmayta,Eline Elshof,Sol Langermann,Emma J De Ruiter,Linde Meyaard,Morten A Karsdal,Stefan Willems,Nicholas Willumsen,Jahangheer Shaik,Chang Song

doi:10.7554/elife.62927

Abstract

Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1. LAIR-2 is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 expressed on immune cells, and that LAIR-2 releases LAIR-1-mediated immune suppression. Analysis of public human datasets shows that collagens, LAIR-1 and LAIR-2 have unique and overlapping associations with survival in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 increases human T cell expansion and effector function in vivo in a mouse xenogeneic-graft versus-host disease model. In humanized mouse tumor models, NC410 reduces tumor growth that is dependent on T cells. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich areas where LAIR-1+ immune cells are localized. Our findings show that NC410 might be a novel strategy for cancer immunotherapy for immune-excluded tumors.

Highlights

The introduction of immune checkpoint blockade therapies in the clinic has increased cancer treatment options for a wide range of tumors, leading to unprecedented and long-lasting clinical responses
A unique set of tumor types emerged that overlapped with those with significant increased LAIR-1 expression, but only partially with the tumor types in that of the total collagen overall survival analysis. These analyses highlighted the complexity of the tumor microenvironment (TME) and supported targeting the collagen:LAIR-1 axis for cancer immunotherapy
Collagen expression and density have been shown to be associated with a worse prognosis either by directly promoting tumor growth or by preventing immune cell infiltration (Lu et al, 2012)

Summary

Introduction

The introduction of immune checkpoint blockade therapies in the clinic has increased cancer treatment options for a wide range of tumors, leading to unprecedented and long-lasting clinical responses. The ECM functions as a scaffold for tissue organization and provides critical biochemical and biomechanical cues that instruct cell growth, survival, differentiation and migration and regulate vascular development and immune function (Hynes, 2009). LAIR-1 is an immune checkpoint broadly expressed on the cell surface of immune cells (Meyaard et al, 1997) that binds to collagen (Lebbink et al, 2006) and molecules with collagen-like domains (Son et al, 2012; Olde Nordkamp et al, 2014b). Besides formation of an ECM-rich and fibrotic tumor niche, TME-expressed collagens can function to promote immune evasion through their direct interaction with LAIR-1. We developed a dimeric LAIR-2 Fc fusion protein, NC410, as a novel immunomedicine to both target tumor ECM and promote T cell function through blockade of LAIR-1-mediated inhibition.

Results

Discussion

Materials and methods

Funding Funder