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

• Published in: The Journal of clinical investigation 2022-04, Vol.132 (8), p.1-18
• Main Authors: Horn, Lucas A, Chariou, Paul L, Gameiro, Sofia R, Qin, Haiyan, Iida, Masafumi, Fousek, Kristen, Meyer, Thomas J, Cam, Margaret, Flies, Dallas, Langermann, Solomon, Schlom, Jeffrey, Palena, Claudia
• Format: Article
• Language: English
• Subjects: Animal models; Apoptosis; Biomedical research; Breast cancer; Carcinoma; CD8 antigen; Cell activation; Cell death; Collagen; Extracellular matrix; Growth factors; Immune checkpoint; Immunoglobulins; Immunotherapy; Infiltration; Ligands; Lymphocytes; Lymphocytes T; Macrophages; Mammary gland; Metastases; PD-L1 protein; Transforming growth factor-b; Tumor microenvironment; Tumors
• ISSN: 0021-9738; 1558-8238
• 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.