Nature communications, 2020-09, Vol.11 (1), p.4520-4520, Article 4520
2020
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- Autor(en) / Beteiligte
- Titel
- Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8 + T cell exhaustion
- Ist Teil von
- Nature communications, 2020-09, Vol.11 (1), p.4520-4520, Article 4520
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-020-18298-8Titel-ID: cdi_doaj_primary_oai_doaj_org_article_219973ddbc6547bdba9bd0531b756cc7
- Format
- –
- Schlagworte
- Adenocarcinoma of Lung - drug therapy, Adenocarcinoma of Lung - genetics, Adenocarcinoma of Lung - immunology, Adenocarcinoma of Lung - pathology, Amino Acid Oxidoreductases - genetics, Amino Acid Oxidoreductases - metabolism, Animals, Antineoplastic Agents, Immunological - pharmacology, Antineoplastic Agents, Immunological - therapeutic use, B7-H1 Antigen - antagonists & inhibitors, B7-H1 Antigen - immunology, Biomarkers, Tumor - metabolism, Cancer, Carcinoma, Lewis Lung - drug therapy, Carcinoma, Lewis Lung - immunology, Carcinoma, Lewis Lung - pathology, CD18 antigen, CD8 antigen, CD8-Positive T-Lymphocytes - immunology, Cell Line, Tumor, Collagen, Collagen - metabolism, Datasets as Topic, Disease Models, Animal, Drug resistance, Drug Resistance, Neoplasm - immunology, Exhaustion, Extracellular matrix, Extracellular Matrix - drug effects, Extracellular Matrix - immunology, Extracellular Matrix - pathology, Female, Gene Knockdown Techniques, HEK293 Cells, Hepatitis A Virus Cellular Receptor 2 - metabolism, Humans, Immunosuppression, Immunotherapy, Lung - immunology, Lung - pathology, Lung Neoplasms - drug therapy, Lung Neoplasms - genetics, Lung Neoplasms - immunology, Lung Neoplasms - pathology, Lungs, Lymphocytes, Lymphocytes T, Male, Melanoma, Metastases, Mice, Mice, Transgenic, PD-1 protein, PD-L1 protein, Programmed Cell Death 1 Receptor - antagonists & inhibitors, Programmed Cell Death 1 Receptor - immunology, Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism, Proto-Oncogene Proteins p21(ras) - genetics, Receptors, Immunologic - genetics, Receptors, Immunologic - metabolism, Ribonucleic acid, RNA, RNA-Seq, SHP-1 protein, Subpopulations, Tumors