Blocking Immune Checkpoint—LAIR1: Disrupting the LAIR1—FXIII-A—Collagen Immunosuppressive Circuit for Enhanced Antitumor Therapeutics

Recent evidence suggests that tumor-associated myeloid cells (TAMCs), which include tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC), play a significant role in cancer immunosuppression and progression. These cells constitute up to 50% of a tumor's total mass and play pivotal roles in dampening the immune response, thereby negatively affecting patient survival. Therefore, targeting TAMCs could overcome the limitations of current cancer treatments. Yet, drug development in this realm remains limited. Our research focuses on leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), prominently expressed on the surface of TAMs, which is essential in mediating the immunosuppressive role of TAMs. We have uncovered a previously unrecognized immunosuppressive LAIR1→ Factor XIII A (FXIII-A)→ Collagen IV circuit across cancer types. The LAIR1 triggers TAMs to release the FXIII-A around tumor cells, which increases tumor collagen IV deposition and structure, shielding the tumors from immune attacks. Inhibiting LAIR1, either through genetic knock-out (LAIR1-/-) or antibody blockade (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 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 Chimeric antigen receptor (CAR) T cell therapy demonstrates enhanced antitumor efficacy in preclinical models resistant to anti-PD-1 treatment. These findings position aLAIR1 as a promising strategy for cancer immunotherapy.