Targeting LAIR1-mediated immunosuppression adds a new weapon to our immunotherapy arsenal
Ezri P. Perrin, … , Hannah K. Dorando, Jacqueline E. Payton
Ezri P. Perrin, … , Hannah K. Dorando, Jacqueline E. Payton
Published August 15, 2025
Citation Information: J Clin Invest. 2025;135(16):e194924. https://doi.org/10.1172/JCI194924.
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Commentary

Targeting LAIR1-mediated immunosuppression adds a new weapon to our immunotherapy arsenal

Abstract

Leukocyte-associated Ig-like receptor 1 (LAIR1) is a collagen-binding inhibitory immune receptor that negatively regulates cellular activation. In this issue of the JCI, Tao et al. show that LAIR1-inhibitory signaling plays an important role in immunosuppressive M2-like tumor-associated macrophages (TAMs) in aggressive brain tumors. LAIR1 KO, antibody blockade, and an immunotherapy that incorporates a LAIR1-inhibitory module into a chimeric antigen receptor (CAR) all led to increased antitumor activity by CAR T cells, reduced M2-like TAMs, altered collagen networks, and increased survival rates in mouse tumor models. These findings demonstrate an innovative immunotherapeutic approach for cancer that leverages LAIR1 inhibition to combat multiple tumor immune evasion strategies.

Authors

Ezri P. Perrin, Hannah K. Dorando, Jacqueline E. Payton

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Figure 1

LAIR1-mediated suppression of the tumor immune response can be targeted by several strategies.

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LAIR1-mediated suppression of the tumor immune response can be targeted ...
(A) In tumors, LAIR1 expressed by macrophages binds collagen IV, promoting an M2-like phenotype and the production of immunosuppressive cytokines, which exhausts nearby T cells. Collagen IV production is increased within the TME, and CAR T cell penetration of the tumor is limited due to both exhaustion and the obstacle that the collagen network presents. (B) Treatments that block LAIR1 collagen binding (such as LAIR1 KO, antibodies against LAIR1, or LAIR1 antagonism via LAIR2 produced by the L2 module of the L2-8R-70CAR T cells) reduce M2 polarization and increase the production of immunostimulating cytokines, activating nearby T cells that attack and kill tumor cells, which are more accessible due to reduced collagen IV levels. These treatments increased survival in several different mouse tumor models.