Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication
Lucas A. Horn, … , Jeffrey Schlom, Claudia Palena
Lucas A. Horn, … , Jeffrey Schlom, Claudia Palena
Published March 1, 2022
Citation Information: J Clin Invest. 2022;132(8):e155148. https://doi.org/10.1172/JCI155148.
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Research Article Immunology

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

Abstract

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.

Authors

Lucas A. Horn, Paul L. Chariou, Sofia R. Gameiro, Haiyan Qin, Masafumi Iida, Kristen Fousek, Thomas J. Meyer, Margaret Cam, Dallas Flies, Solomon Langermann, Jeffrey Schlom, Claudia Palena

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Figure 5

Remodeling of collagen in tumors treated with NC410 plus bintrafusp alfa therapy.

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Remodeling of collagen in tumors treated with NC410 plus bintrafusp alfa...
(A) Representative images of immunofluorescence-based staining of denatured collagen utilizing a linearized collagen hybridizing peptide (CHP, magenta) in MC38 tumors collected as indicated in Figure 2A. White dash–outlined squares identify magnified regions in bottom images. (B) Mean fluorescence intensity value of denatured collagen across treatment groups; 10 regions of interest (ROIs) randomly selected within each tumor section; n = 3 tumors per treatment group. For violin plots, dashed line displays the median and dotted lines display quartiles. (C) Staining of denatured collagen in control MC38 tumors utilizing linearized CHP peptide or nonlinearized CHP as a negative control. (D) Staining of denatured collagen in control MC38 tumors in the absence or presence of NC410 to rule out competition for binding to collagens. (E) Total collagen content measured with CHP staining after heat retrieval in MC38 tumors collected 1 day following the second dose of treatments, as indicated in Figure 2A. DAPI staining of nuclei (cyan) is shown. (F) Representative images of MC38 tumors treated with control, NC410, bintrafusp alfa, and NC410 plus bintrafusp alfa analyzed for collagen expression by trichrome staining. Scale bars: 20 μm (A, bottom panels, and D), 50 μm (A, C, and E), and 100 μm (F). ****P ≤ 0.0001 by 1-way ANOVA followed by Tukey’s post hoc test in B.