Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication
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
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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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 4

NC410 plus bintrafusp alfa reduces tumor infiltration with tumor-associated M2 macrophages.

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NC410 plus bintrafusp alfa reduces tumor infiltration with tumor-associa...
(A) Flow cytometry analysis of total macrophages and CD38+ macrophages in MC38 tumors collected on day 17 following treatment with NC410 (250 μg) and/or bintrafusp alfa (250 μg) on days 9, 11, and 13. Graphs show the number of cells per mg tumor weight; n = 7 (control, NC410, bintrafusp alfa), n = 5 (NC410 + bintrafusp alfa). For violin plots, dashed line displays the median and dotted lines display quartiles. (B) Top 10 activated GO gene pathways in M1 clusters identified by scRNA-seq in the NC410 plus bintrafusp alfa versus the control group. UMAP plots showing (C) expression of Mrc1 and Cd163 genes used to identify M2 cell clusters by scRNA-seq, and (D) variations in their expression across treatment groups. (E) Frequency of subpopulations of M2 macrophages according to their expression of Cd163 and Mrc1. (F) Selected activated GO/REACTOME/KEGG/HALLMARK gene pathways in Cd163neg Mrc1pos M2 clusters identified by scRNA-seq in the NC410 plus bintrafusp alfa versus the control group. (G) Bubble plot representation of the top 30 upregulated and top 20 downregulated genes (logFC ≥ 0.25 or ≤ –0.25 and P value ≤ 0.05) in Cd163neg Mrc1pos M2 clusters from the NC410 plus bintrafusp alfa group versus the control group. Bubble size shows percentage of cells expressing the indicated gene; color intensity represents scaled expression levels. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001 by 1-way ANOVA followed by Tukey’s post hoc test in A.