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 1

NC410 and bintrafusp alfa synergize for effective tumor control.

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NC410 and bintrafusp alfa synergize for effective tumor control. (A and ...
(A and F) Representative images of MC38 and EMT6 tumors analyzed for collagen (trichrome staining), NC410-biotin, and control IgG-biotin staining. Scale bars: 50 μm (A) and 100 μm (F). (B) Treatment schedule for mice bearing MC38 tumors. Individual tumor growth and number of cures (C) and average tumor growth (D) are shown; n = 5 mice/group (control) or n = 6 (all other groups). Data are representative of 1 of 2 independent experiments. (E) Left: Cured mice were rechallenged s.c. with MC38 and LLC tumor cells. Right: Control C57BL/6 mice were injected s.c. with either MC38 or LLC tumor cells. Graphs show individual tumor growth and number of mice free of tumor. (G) Treatment schedule for mice bearing s.c. EMT6 tumors. Individual tumor growth and number of cures (H) and average tumor growth (I) are shown; n = 8 mice/group (control) or n = 9 (all other groups). (J) Left: Cured mice from the combination group were rechallenged s.c. with EMT6 and 4T1 tumor cells. Right: Control BALB/c mice were injected s.c. with either EMT6 or 4T1 tumor cells. Graph shows individual tumor growth. Error bars indicate SEM of biological replicates. *P ≤ 0.05; **P ≤ 0.01; ****P ≤ 0.0001 by 2-way ANOVA (D and I).