Targeting human leukocyte antigen G with chimeric antigen receptors of natural killer cells convert immunosuppression to ablate solid tumors.

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  • Additional Information
    • Source:
      Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Print Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE
    • Publication Information:
      Publication: 2020- : London, United Kingdom : BMJ Publishing Group Ltd.
      Original Publication: London : BioMed Central, 2013-
    • Subject Terms:
      Antigens, Neoplasm/*immunology ; HLA Antigens/*metabolism ; Immunosuppression Therapy/*methods ; Immunotherapy/*methods ; Killer Cells, Natural/*metabolism ; Neoplasms/*immunology ; Receptors, Chimeric Antigen/*metabolism; Animals ; Disease Models, Animal ; Humans ; Male ; Mice ; Transfection ; Tumor Microenvironment
    • Abstract:
      Background: Immunotherapy against solid tumors has long been hampered by the development of immunosuppressive tumor microenvironment, and the lack of a specific tumor-associated antigen that could be targeted in different kinds of solid tumors. Human leukocyte antigen G (HLA-G) is an immune checkpoint protein (ICP) that is neoexpressed in most tumor cells as a way to evade immune attack and has been recently demonstrated as a useful target for chimeric antigen receptor (CAR)-T therapy of leukemia by in vitro studies. Here, we design and test for targeting HLA-G in solid tumors using a CAR strategy.
      Methods: We developed a novel CAR strategy using natural killer (NK) cell as effector cells, featuring enhanced cytolytic effect via DAP12-based intracellular signal amplification. A single-chain variable fragment (scFv) against HLA-G is designed as the targeting moiety, and the construct is tested both in vitro and in vivo on four different solid tumor models. We also evaluated the synergy of this anti-HLA-G CAR-NK strategy with low-dose chemotherapy as combination therapy.
      Results: HLA-G CAR-transduced NK cells present effective cytolysis of breast, brain, pancreatic, and ovarian cancer cells in vitro, as well as reduced xenograft tumor growth with extended median survival in orthotopic mouse models. In tumor coculture assays, the anti-HLA-G scFv moiety promotes Syk/Zap70 activation of NK cells, suggesting reversal of the HLA-G-mediated immunosuppression and hence restoration of native NK cytolytic functions. Tumor expression of HLA-G can be further induced using low-dose chemotherapy, which when combined with anti-HLA-G CAR-NK results in extensive tumor ablation both in vitro and in vivo. This upregulation of tumor HLA-G involves inhibition of DNMT1 and demethylation of transporter associated with antigen processing 1 promoter.
      Conclusions: Our novel CAR-NK strategy exploits the dual nature of HLA-G as both a tumor-associated neoantigen and an ICP to counteract tumor spread. Further ablation of tumors can be boosted when combined with administration of chemotherapeutic agents in clinical use. The readiness of this novel strategy envisions a wide applicability in treating solid tumors.
      Competing Interests: Competing interests: No, there are no competing interests.
      (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)
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    • Contributed Indexing:
      Keywords: combination; drug therapy; immunotherapy; killer cells; natural
    • Accession Number:
      0 (Antigens, Neoplasm)
      0 (HLA Antigens)
      0 (Receptors, Chimeric Antigen)
    • Publication Date:
      Date Created: 20211019 Date Completed: 20220112 Latest Revision: 20220112
    • Publication Date:
      20221213
    • Accession Number:
      PMC8524382
    • Accession Number:
      10.1136/jitc-2021-003050
    • Accession Number:
      34663641