CELL INTELLIGENCE · 肿瘤细胞治疗研究

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-1 2 expressed by tumor cells simultaneously drives TME fibrosis and inhibits migration of immune cells to brain tumors, thus achieving powerful immune exclusion 3 .

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 therapy 4 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>SHP2>JNK>CXCL16 and/or LOXL1 axis as a therapeutic target for sensitizing glioma to immunotherapy.