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 2

Expression of target molecules and treatment effect on tumor immune infiltrates.

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Expression of target molecules and treatment effect on tumor immune infi...
(A) Treatment schedule for mice bearing MC38 tumors. (B) Immunofluorescence-based analysis of harvested tumors for human IgG, indicating presence of therapeutic agents. Graph shows the fluorescence signal across 15 regions of interest (ROIs) randomly selected within each tumor section, n = 2–3 tumors per treatment group, normalized to the average signal in the control group. (C) Representative images of MC38 tumors. Scale bar: 50 μm. (D) scRNA-seq profiling of tumor-infiltrating CD45+ cells isolated from tumors treated as indicated in A. UMAP plots for all treatment groups combined and analyzed as described in the Methods section, showing selected identified immune cell subset clusters with events colored according to cell type. (E) Frequency of selected cell subsets identified by scRNA-seq analysis from MC38 tumors treated as indicated in A. (F and G) Expression of selected genes of relevance by scRNA-seq in single-color UMAP plots (F) or in bubble plot representation across selected immune cell subset clusters. Bubble size shows percentage of cells expressing the indicated gene; color intensity represents scaled expression levels. Data from scRNA-seq analysis are from a single experiment. (H) Flow cytometry analysis of LAIR-1 expression on indicated immune cell subsets in the blood, spleen, and tumors from MC38 and EMT6 tumor–bearing mice; n = 5 mice/group (MC38), n = 4/group (EMT6). Tissues for analysis were collected on day 12 prior to any treatment. For violin plots, dashed line displays the median and dotted lines display quartiles. Data from MC38 spleen and tumor flow cytometry are representative of 1 of 2 independent experiments.