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; Don L. Gibbons

doi:10.1038/s41467-020-18298-8

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, Don L. Gibbons

Research output: Contribution to journal › Article › peer-review

199 Scopus citations

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.

Original language	English (US)
Article number	4520
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18298-8
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

MD Anderson CCSG core facilities

Bioinformatics Shared Resource
Functional Genomics Core

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10.1038/s41467-020-18298-8

Cite this

Peng, D. H., Rodriguez, B. L., Diao, L., Chen, L., Wang, J., Byers, L. A., Wei, Y., Chapman, H. A., Yamauchi, M., Behrens, C., Raso, G., Soto, L. M. S., Cuentes, E. R. P., Wistuba, I. I., Kurie, J. M., & Gibbons, D. L. (2020). Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8⁺ T cell exhaustion. Nature communications, 11(1), Article 4520. https://doi.org/10.1038/s41467-020-18298-8

Peng, DH , Rodriguez, BL , Diao, L, Chen, L, Wang, J , Byers, LA, Wei, Y, Chapman, HA, Yamauchi, M, Behrens, C , Raso, G , Soto, LMS, Cuentes, ERP, Wistuba, II , Kurie, JM & Gibbons, DL 2020, 'Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8⁺ T cell exhaustion', Nature communications, vol. 11, no. 1, 4520. https://doi.org/10.1038/s41467-020-18298-8

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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.",

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