Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion

David H. Peng, Bertha Leticia Rodriguez, Lixia Diao, Limo Chen, Jing Wang, Lauren A. Byers, Ying Wei, Harold A. Chapman, Mitsuo Yamauchi, Carmen Behrens, Gabriela Raso, Luisa Maren Solis Soto, Edwin Roger Parra Cuentes, Ignacio I. Wistuba, Jonathan M. Kurie and Don L. Gibbons ()
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David H. Peng: The University of Texas MD Anderson Cancer Center
Bertha Leticia Rodriguez: The University of Texas MD Anderson Cancer Center
Lixia Diao: The University of Texas MD Anderson Cancer Center
Limo Chen: The University of Texas MD Anderson Cancer Center
Jing Wang: The University of Texas MD Anderson Cancer Center
Lauren A. Byers: The University of Texas MD Anderson Cancer Center
Ying Wei: UCSF Cardiovascular Research Institute
Harold A. Chapman: UCSF Cardiovascular Research Institute
Mitsuo Yamauchi: University of North Carolina at Chapel Hill
Carmen Behrens: The University of Texas MD Anderson Cancer Center
Gabriela Raso: The University of Texas MD Anderson Cancer Center
Luisa Maren Solis Soto: The University of Texas MD Anderson Cancer Center
Edwin Roger Parra Cuentes: The University of Texas MD Anderson Cancer Center
Ignacio I. Wistuba: The University of Texas MD Anderson Cancer Center
Jonathan M. Kurie: The University of Texas MD Anderson Cancer Center
Don L. Gibbons: The University of Texas MD Anderson Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18298-8

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