Blocking Immunoinhibitory Receptor LILRB2 Reprograms Tumor-Associated Myeloid Cells and Promotes Antitumor Immunity

Details

• Personal Author:
  Aaronson S ; Alsina-Beauchamp D ; Arase H ; Chen H-M ; Chen S-H ; Duty JA ; Flavell R ; Flores R ; Hu H-M ; Kang K ; Mai S ; Moran T ; Mungamuri SK ; Pan P-Y ; Ramanathan S ; van der Touw W ; Wang YS ; Zhang B ; Zhang J
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Antibodies Blood Genetics Immune System Neoplasms Occupational Health Safety
• Keywords:
  Blood Cells Cell Signaling Genes Immune Reaction Myeloid Tissue Tumors
• ISSN:
  0021-9738
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  Connecticut ; New York ; Oregon ; OSHA Region 1 ; OSHA Region 10 ; OSHA Region 2 ; OSHA Region 6 ; Texas
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  128
• Issue:
  12
• NIOSHTIC Number:
  nn:20055200
• Citation:
  J Clin Invest 2018 Dec; 128(12):5647-5662
• Contact Point Address:
  Ping-Ying Pan or Shu-Hsia Chen, Immunotherapy Research Center, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, USA
• Email:
  ppan@houstonmethodist.org
• Federal Fiscal Year:
  2019
• Performing Organization:
  Icahn School of Medicine at Mount Sinai, New York
• Peer Reviewed:
  True
• Start Date:
  20160901
• Source Full Name:
  Journal of Clinical Investigation
• End Date:
  20210831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:aa93b41a8211790fd29dfe50383d721967922cbd40e27277ccf5118e07389f98abcd787c26234acedd6f133b9d9f55699e5bd53d660a5494a6afb5e37742966e
• Download URL:
  https://stacks.cdc.gov/view/cdc/217557/cdc_217557_DS1.pdf
• File Type:
  [PDF - 6.01 MB ]