1. Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion.
- Author
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Peng, David H, Rodriguez, Bertha Leticia, Diao, Lixia, Chen, Limo, Wang, Jing, Byers, Lauren A, Wei, Ying, Chapman, Harold A, Yamauchi, Mitsuo, Behrens, Carmen, Raso, Gabriela, Soto, Luisa Maren Solis, Cuentes, Edwin Roger Parra, Wistuba, Ignacio I, Kurie, Jonathan M, and Gibbons, Don L
- Subjects
Lung ,CD8-Positive T-Lymphocytes ,Cell Line ,Tumor ,Extracellular Matrix ,Animals ,Mice ,Transgenic ,Humans ,Mice ,Carcinoma ,Lewis Lung ,Lung Neoplasms ,Disease Models ,Animal ,Collagen ,Amino Acid Oxidoreductases ,Receptors ,Immunologic ,Drug Resistance ,Neoplasm ,Female ,Male ,Proto-Oncogene Proteins p21(ras) ,Protein Tyrosine Phosphatase ,Non-Receptor Type 6 ,Gene Knockdown Techniques ,HEK293 Cells ,Programmed Cell Death 1 Receptor ,Datasets as Topic ,Biomarkers ,Tumor ,Hepatitis A Virus Cellular Receptor 2 ,Antineoplastic Agents ,Immunological ,B7-H1 Antigen ,Adenocarcinoma of Lung ,RNA-Seq ,Cell Line ,Tumor ,Transgenic ,Carcinoma ,Lewis Lung ,Disease Models ,Animal ,Receptors ,Immunologic ,Drug Resistance ,Neoplasm ,Protein Tyrosine Phosphatase ,Non-Receptor Type 6 ,Biomarkers ,Antineoplastic Agents ,Immunological - 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.
- Published
- 2020