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 6

Inhibition of TGF-β and PD-L1 are both required for optimal tumor control in combination with NC410.

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Inhibition of TGF-β and PD-L1 are both required for optimal tumor contro...
MC38 tumor–bearing mice were administered indicated doses of NC410, bintrafusp alfa, anti–PD-L1, or TGF-β trap control on days 9, 11, and 13 after tumor injection. Graphs show (A) individual tumor growth and number of cures in each group, and (B) average tumor growth; n = 6 mice/group (bintrafusp alfa, NC410 + bintrafusp alfa) or n = 7 (control, anti–PD-L1, TGF-β trap control, NC410, NC410 + anti–PD-L1, NC410 + TGF-β trap control). Data are representative of 1 of 2 independent experiments. Error bars indicate SEM of biological replicates. *P ≤ 0.05; ***P ≤ 0.001; ****P ≤ 0.0001 by 2-way ANOVA. (C) Treatment schedule of indicated therapeutic agents; CD45+ cells isolated from MC38 tumors collected on day 12 were used for scRNA-seq analysis. (D) Frequency of effector CD4+, CD8+, T regulatory (Treg) cells, NK and NKT cell clusters as determined by scRNA-seq, shown as a percentage of total CD45+ cells. (E) Frequency of subpopulations of M2 macrophages according to their expression of Cd163 and Mrc1. (F). Bubble plot representation of all genes differentially expressed (logFC ≥ 0.25 or ≤ –0.25 and P value ≤ 0.05) in total CD45+ cells from the NC410 plus bintrafusp alfa group versus all other groups. Bubble size shows percentage of cells expressing the indicated gene; color intensity represents scaled expression levels. (G) UMAP plots showing expression of selected genes by scRNA-seq analysis on CD45+ cells in each treatment group. Data from scRNA-seq analysis are from a single experiment; control and NC410 plus bintrafusp alfa groups from Figures 2–4 are shown for comparison.