Faculty, Staff and Student Publications

Publication Date

8-1-2024

Journal

Molecular Cancer Therapeutics

Abstract

We recently reported that resistance to PD-1 blockade in a refractory lung cancer-derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1). Thus, we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. In this study, we report that LAIR1 is associated with tumor stroma and is highly expressed by intratumoral myeloid cells in both human tumors and mouse models of cancer. Stroma-associated myeloid cells exhibit a suppressive phenotype and correlate with LAIR1 expression in human cancer. NGM438, a novel humanized LAIR1 antagonist mAb, elicits myeloid inflammation and allogeneic T-cell responses by binding to LAIR1 and blocking collagen engagement. Furthermore, a mouse-reactive NGM438 surrogate antibody sensitized refractory KP mouse lung tumors to anti-PD-1 therapy and resulted in increased intratumoral CD8+ T-cell content and inflammatory gene expression. These data place LAIR1 at the intersection of stroma and suppressive myeloid cells and support the notion that blockade of the LAIR1/collagen axis can potentially address resistance to checkpoint inhibitor therapy in the clinic.

Keywords

Animals, Female, Humans, Mice, Cell Line, Tumor, Collagen, Disease Models, Animal, Immune Checkpoint Inhibitors, Lung Neoplasms, Neoplasms, Programmed Cell Death 1 Receptor, Receptors, Immunologic, Antineoplastic Agents

DOI

10.1158/1535-7163.MCT-23-0866

PMID

38648067

PMCID

PMC11293989

PubMedCentral® Posted Date

2-1-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

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