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
Included in
Bioinformatics Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Oncology Commons