Abstract
Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenocarcinoma of Lung / drug therapy*
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Adenocarcinoma of Lung / genetics
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Adenocarcinoma of Lung / immunology
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Adenocarcinoma of Lung / pathology
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Amino Acid Oxidoreductases / genetics
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Amino Acid Oxidoreductases / metabolism
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Animals
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Antineoplastic Agents, Immunological / pharmacology*
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Antineoplastic Agents, Immunological / therapeutic use
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B7-H1 Antigen / antagonists & inhibitors
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B7-H1 Antigen / immunology
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Biomarkers, Tumor / metabolism
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CD8-Positive T-Lymphocytes / immunology*
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Carcinoma, Lewis Lung / drug therapy
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Carcinoma, Lewis Lung / immunology
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Carcinoma, Lewis Lung / pathology
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Cell Line, Tumor
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Collagen / metabolism*
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Datasets as Topic
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Disease Models, Animal
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Drug Resistance, Neoplasm / immunology*
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Extracellular Matrix / drug effects
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Extracellular Matrix / immunology
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Extracellular Matrix / pathology
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Female
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Gene Knockdown Techniques
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HEK293 Cells
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Hepatitis A Virus Cellular Receptor 2 / metabolism
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Humans
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Lung / immunology
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Lung / pathology
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / genetics
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Lung Neoplasms / immunology
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Lung Neoplasms / pathology
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Male
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Mice
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Mice, Transgenic
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Programmed Cell Death 1 Receptor / antagonists & inhibitors
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Programmed Cell Death 1 Receptor / immunology
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
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Proto-Oncogene Proteins p21(ras) / genetics
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RNA-Seq
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism*
Substances
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Antineoplastic Agents, Immunological
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B7-H1 Antigen
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Biomarkers, Tumor
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Cd274 protein, mouse
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HAVCR2 protein, human
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Havcr2 protein, mouse
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Hepatitis A Virus Cellular Receptor 2
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LAIR-2 receptor
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Receptors, Immunologic
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leukocyte-associated immunoglobulin-like receptor 1
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Collagen
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Amino Acid Oxidoreductases
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Loxl2 protein, mouse
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Ptpn6 protein, mouse
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)