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 3

Combination therapy increases infiltration with activated CD8+ T cells.

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Combination therapy increases infiltration with activated CD8+ T cells. ...
(A) UMAP plots showing CD4+ and CD8+ T cells, T regulatory (Treg) cells, NK and NKT cell clusters as identified by scRNA-seq analysis from MC38 tumors treated as in Figure 2A. (B) Frequency of indicated immune cell subsets, as a percentage of total CD45+ cells. (C) Flow cytometry analysis of indicated immune infiltrating cells or (E) analysis of CD8+ T cells for expression of Ki67 or granzyme B (GzmB) 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). (D) UMAP plots showing expression of selected genes by scRNA-seq. (F) Representative images of CD8+ T cell infiltrates (magenta) in MC38 tumors treated as indicated in Figure 2A. DAPI (cyan) was used as a nuclear stain. Scale bars: 100 μm and 10 μm (insets). (G) IFN-γ ELISPOT analysis of spleens from MC38 tumor–bearing mice treated as indicated, against the p15E tumor antigen; n = 6/group. Representative images of well signals from 2 individuals per group are displayed. (H) Average tumor growth of MC38 tumors untreated or treated with NC410 plus bintrafusp alfa with or without depleting antibodies for CD4+, CD8+, or NK cells; n = 6 in the NK depletion group; n = 7 in all other groups. For violin plots, dashed line displays the median and dotted lines display quartiles. Error bars indicate SEM of biological replicates. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001 by 1-way ANOVA followed by Tukey’s post hoc test in C, E, and G and 2-way ANOVA in H.