Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1-mediated tumor eradication

J Clin Invest. 2022 Apr 15;132(8):e155148. doi: 10.1172/JCI155148.


Collagens in the extracellular matrix (ECM) provide a physical barrier to tumor immune infiltration, while also acting as a ligand for immune inhibitory receptors. Transforming growth factor-β (TGF-β) is a key contributor to shaping the ECM by stimulating the production and remodeling of collagens. TGF-β activation signatures and collagen-rich environments have both been associated with T cell exclusion and lack of responses to immunotherapy. Here, we describe the effect of targeting collagens that signal through the inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) in combination with blockade of TGF-β and programmed cell death ligand 1 (PD-L1). This approach remodeled the tumor collagenous matrix, enhanced tumor infiltration and activation of CD8+ T cells, and repolarized suppressive macrophage populations, resulting in high cure rates and long-term tumor-specific protection across murine models of colon and mammary carcinoma. The results highlight the advantage of direct targeting of ECM components in combination with immune checkpoint blockade therapy.

Trial registration: NCT00001846.

Keywords: Cancer immunotherapy; Immunology.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen* / genetics
  • B7-H1 Antigen* / metabolism
  • Immunotherapy / methods
  • Ligands
  • Mice
  • Neoplasms* / therapy
  • Receptors, Immunologic* / genetics
  • Receptors, Immunologic* / metabolism
  • Transforming Growth Factor beta / metabolism
  • Tumor Microenvironment*


  • B7-H1 Antigen
  • Ligands
  • Receptors, Immunologic
  • Transforming Growth Factor beta
  • leukocyte-associated immunoglobulin-like receptor 1

Associated data


Grant support

CrossRef Funder ID: 10.13039/100004755