A dual pronged approach to cancer immune exclusion: tumor-derived LAIR-1 simultaneously drives fibrosis and blocks immune recruitment in glioma

<title>Abstract</title> <p>Glioblastoma is among the most lethal human malignancies. Immune-based therapies have failed due to a strong immunosuppressive tumor microenvironment (TME)1. We uncovered that LAIR-12 expressed by tumor cells simultaneously drives TME fibrosis and inhibits migration of immune cells to brain tumors, thus achieving powerful immune exclusion3. We demonstrate that glioma-cell-specific LAIR-1 knockdown (KD), but not LAIR-1 KD from host cells, significantly extends survival in an immune-dependent manner. Glioma-cell-specific LAIR-1 signals through SHP2 to activate JNK –which on one hand sustains high levels of Lysyl Oxidase-Like 1 and collagen I to block immune cells’ entry– and on the other hand suppresses STAT3 signaling. In the absence of LAIR-1, gliomas’ collagen-dense ECM becomes disassembled and, through STAT3-driven upregulation of ADAM10 and ADAM17, promotes release of CXCL16, and recruitment of NK cells and cytotoxic T cells. Combining LAIR-1 KD with immune-stimulatory gene therapy4 achieved 100% long-term survival with durable immunological memory in immunocompetent mice. Pharmacological SHP2 inhibition in LAIR-1 WT mouse and human glioma cells recapitulated the LAIR-1 KD molecular phenotype and similarly potentiated gene therapy. These findings define LAIR-1 as a tumor-cell-intrinsic pro-fibrotic and immunosuppressive checkpoint and identify the LAIR-1&gt;SHP2&gt;JNK&gt;CXCL16 and/or LOXL1 axis as a therapeutic target for sensitizing glioma to immunotherapy.</p>