Myeloid cells respond to multiple environmental cues which modulate their phenotype and Chen et al. demonstrate that LILRB2, a myeloid signaling receptor which naturally binds HLA class I, serves as a checkpoint, directing myeloid cells toward an anti-inflammatory phenotype. Antibody blockade of LILRB2 during macrophage maturation enhanced NF-κB/STAT1 activation, resulting in multiple gene expression changes including reduction of PD-L1 expression and decreased STAT6 activation, shifting cells away from the M2 phenotype and enhancing antitumor efficacy in humanized or Lilrb2-transgenic mice when combined with anti-PD-1/anti-PD-L1.
Tumor-associated myeloid cells maintain immunosuppressive microenvironments within tumors. Identification of myeloid-specific receptors to modulate tumor-associated macrophage and myeloid-derived suppressor cell (MDSC) functions remains challenging. The leukocyte immunoglobulin-like receptor B (LILRB) family members are negative regulators of myeloid cell activation. We investigated how LILRB targeting could modulate tumor-associated myeloid cell function. LILRB2 antagonism inhibited receptor-mediated activation of SHP1/2 and enhanced proinflammatory responses. LILRB2 antagonism also inhibited AKT and STAT6 activation in the presence of M-CSF and IL-4. Transcriptome analysis revealed that LILRB2 antagonism altered genes involved in cell cytoskeleton remodeling, lipid/cholesterol metabolism, and endosomal sorting pathways, as well as changed differentiation gene networks associated with inflammatory myeloid cells as opposed to their alternatively activated phenotype. LILRB2 blockade effectively suppressed granulocytic MDSC and Treg infiltration and significantly promoted in vivo antitumor effects of T cell immune checkpoint inhibitors. Furthermore, LILRB2 blockade polarized tumor-infiltrating myeloid cells from non-small cell lung carcinoma tumor tissues toward an inflammatory phenotype. Our studies suggest that LILRB2 can potentially act as a myeloid immune checkpoint by reprogramming tumor-associated myeloid cells and provoking antitumor immunity.
Author Info: (1) Immunotherapy Research Center, and. Cancer Center, Houston Methodist Research Institute, Houston, Texas, USA. (2) Department of Oncological Sciences. (3) Department of Oncologi
Author Info: (1) Immunotherapy Research Center, and. Cancer Center, Houston Methodist Research Institute, Houston, Texas, USA. (2) Department of Oncological Sciences. (3) Department of Oncological Sciences. (4) Immunotherapy Research Center, and. Cancer Center, Houston Methodist Research Institute, Houston, Texas, USA. (5) Department of Oncological Sciences. (6) Immunotherapy Research Center, and. Cancer Center, Houston Methodist Research Institute, Houston, Texas, USA. (7) Department of Oncological Sciences. (8) Department of Microbiology, and. (9) Department of Oncological Sciences. (10) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. (11) Department of Microbiology, and. (12) Department of Immunobiology, Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA. (13) Department of Oncological Sciences. (14) Laboratory of Cancer Immunobiology, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon, USA. (15) Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan. (16) Department of Thoracic Surgery, Mount Sinai Hospital, New York, New York, USA. (17) Department of Thoracic Surgery, Mount Sinai Hospital, New York, New York, USA. Department of General Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA. (18) Immunotherapy Research Center, and. Cancer Center, Houston Methodist Research Institute, Houston, Texas, USA. (19) Immunotherapy Research Center, and. Cancer Center, Houston Methodist Research Institute, Houston, Texas, USA.
