Enhancing antitumor efficacy by intratumoral delivering LAIR1 inhibitory signaling - PROJECT SUMMARY 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 the tumor's total mass in glioblastoma (GBM) 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. We hypothesize that LAIR1 is a new inhibitory immune checkpoint molecule that controls the pro-tumor function of the TAMCs. This study will elucidate mechanisms of the signaling axis of LAIR1 and its binding partners in tumor immunosuppression and progression and determine if inhibiting this molecule using 3-in-1 triple-functional CAR (L2-8R-70CAR (targeting tumor cells, enhancing CAR T cell tumor trafficking, and delivering LAIR1 blocking to TAMC inhibition) can reshape the tumor microenvironment and induce a profound antitumor response. Two aims are proposed: Aim 1: Determine the role of LAIR1 in GBM immunosuppression. Aim 2: Overcome the blood-brain barrier (BBB) using our 8R-70CAR T cells, currently being tested in a phase I clinical trial (FDA- IND#23881, NCT05353530), to deliver LAIR1 inhibitory signaling in GBM. Successfully completing this study will advance our understanding of the LAIR1 signaling axis and its role in tumor immunosuppression and progression. It will validate the use of 3-in-1, L2-8R-70CAR T cells in overcoming the blood-brain barrier to deliver targeted LAIR1 inhibition and demonstrate the potential of triple-functional CAR T cells to reshape the tumor microenvironment and induce a robust antitumor response.
