Skip to main content
eScholarship
Open Access Publications from the University of California

UCSF

UC San Francisco Previously Published Works bannerUCSF

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

  • Author(s): Peng, David H;
  • Rodriguez, Bertha Leticia;
  • Diao, Lixia;
  • Chen, Limo;
  • Wang, Jing;
  • Byers, Lauren A;
  • Wei, Ying;
  • Chapman, Harold A;
  • Yamauchi, Mitsuo;
  • Behrens, Carmen;
  • Raso, Gabriela;
  • Soto, Luisa Maren Solis;
  • Cuentes, Edwin Roger Parra;
  • Wistuba, Ignacio I;
  • Kurie, Jonathan M;
  • Gibbons, Don L
  • et al.
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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View