期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-18298-8
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资金
- CPRIT [RP150405]
- NIH [R37 CA214609]
- Uniting Against Lung Cancer/Lung Cancer Research Foundation award
- Rexanna's Foundation for Fighting Lung Cancer
- CPRIT-MIRA [RP160652]
- UT Lung Cancer SPORE NCI [P50 CA070907]
- Cancer Center Support Grant (CCSG) [CA016672]
- Mary K. Chapman Foundation
- Jeanne F. Shel by Scholarship Fund
- philanthropic contributions to the University of Texas MD Anderson Lung Cancer Moon Shots Program
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.
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