EXTH-58. BLOCKING IMMUNE CHECKPOINT— LAIR1: DISRUPTING THE LAIR1—FXIII-A—COLLAGEN IMMUNOSUPPRESSIVE CIRCUIT FOR ENHANCED ANTITUMOR THERAPEUTICS

Abstract BACKGROUND Recent evidence indicates that tumor-associated myeloid cells (TAMCs), including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), play a crucial role in glioblastoma (GBM) immunosuppression and progression. These cells can constitute up to 50% of the total mass in GBM tumors and are pivotal in dampening the immune response, which negatively impacts patient survival. Targeting TAMCs represents a promising strategy to overcome the limitations of current cancer treatments. However, drug development in this area remains limited. Our study focuses on Leukocyte-Associated Immunoglobulin-like Receptor 1 (LAIR1), a novel immune checkpoint overexpressed on TAMCs within GBM. We comprehensively analyze LAIR1’s inhibitory role in cancer progression, highlighting its potential as a therapeutic target. METHODS Both in vitro and in vivo experiments were conducted. LAIR1 wild-type (LAIR1+/+) and knock-out (LAIR1-/-) tumor models were tested for antitumor response and intratumoral immune landscape. We also utilized 2D and 3D cultures to evaluate the effects of antibody blockade (aLAIR1) alone and in combination with CAR-T therapy (8R-70CAR) in both human and mouse GBM models. RESULTS We have uncovered a previously unrecognized immunosuppressive LAIR1→ Factor XIII A (FXIII-A)→ Collagen IV circuit across cancer types. Inhibiting LAIR1, either through genetic LAIR1-/- or aLAIR1, effectively disrupts this immunosuppressive pathway and results in enhanced peripheral and tumor-infiltrating memory CD8 T cell populations, a phenotypic shift of TAMs towards an M1 profile, and a decrease in tumor collagen deposition. These collective effects contribute to the normalization of the TME and facilitate improved interactions between T cells and tumor cells, leading to a more effective antitumor response. Notably, using aLAIR1 as a standalone intervention or combined with CAR T cell therapy demonstrates enhanced antitumor efficacy in preclinical models resistant to chemo-radiation and anti-PD-1 treatments. CONCLUSIONS We discovered a novel mechanism by which LAIR1 contributes to GBM progression. LAIR1 blockade holds promise in reversing suppressive TME and serving as a therapeutic strategy.