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

Author

Listed:
  • 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
    The University of Texas MD Anderson Cancer Center)

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.

Suggested Citation

  • 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 So, 2020. "Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18298-8
    DOI: 10.1038/s41467-020-18298-8
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    Cited by:

    1. Qi Zhang & Rober Abdo & Cristiana Iosef & Tomonori Kaneko & Matthew Cecchini & Victor K. Han & Shawn Shun-Cheng Li, 2022. "The spatial transcriptomic landscape of non-small cell lung cancer brain metastasis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Stefanie Hiltbrunner & Lena Cords & Sabrina Kasser & Sandra N. Freiberger & Susanne Kreutzer & Nora C. Toussaint & Linda Grob & Isabelle Opitz & Michael Messerli & Martin Zoche & Alex Soltermann & Mar, 2023. "Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Michael Papanicolaou & Amelia L. Parker & Michelle Yam & Elysse C. Filipe & Sunny Z. Wu & Jessica L. Chitty & Kaitlin Wyllie & Emmi Tran & Ellie Mok & Audrey Nadalini & Joanna N. Skhinas & Morghan C. , 2022. "Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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