Exploiting Human NK Cells in Tumor Therapy: Frontiers in Immunology

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NK cells play an important role in the innate defenses against tumor growth and metastases. Human NK cell activation and function are regulated by an array of HLA class I-specific inhibitory receptors and activating receptors recognizing ligands expressed de novo on tumor or virus-infected cells. NK cells have been exploited in immunotherapy of cancer, including: (1) the in vivo infusion of IL-2 or IL-15, cytokines inducing activation and proliferation of NK cells that are frequently impaired in cancer patients. Nonetheless, the significant toxicity experienced, primarily with IL-2, limited their use except for combination therapies, e.g., IL-15 with checkpoint inhibitors; (2) the adoptive immunotherapy with cytokine-induced NK cells had effect on some melanoma metastases (lung), while other localizations were not affected; (3) a remarkable evolution of adoptive cell therapy is represented by NK cells engineered with CAR-targeting tumor antigens (CAR-NK). CAR-NK cells complement CAR-T cells as they do not cause GvHD and may be obtained from unrelated donors. Accordingly, CAR-NK cells may represent an “off-the-shelf” tool, readily available for effective tumor therapy; (4) the efficacy of adoptive cell therapy in cancer is also witnessed by the αβT cell- and B cell-depleted haploidentical HSC transplantation in which the infusion of donor NK cells and γδT cells, together with HSC, sharply reduces leukemia relapses and infections; (5) a true revolution in tumor therapy is the use of mAbs targeting checkpoint inhibitors including PD-1, CTLA-4, the HLA class I-specific KIR, and NKG2A. Since PD-1 is expressed not only by tumor-associated T cells but also by NK cells, its blocking might unleash NK cells playing a crucial effector role against HLA class I-deficient tumors that are undetectable by T cells. © Copyright © 2020 Vacca, Pietra, Tumino, Munari, Mingari and Moretta.
Original languageEnglish
JournalFront. Immunol.
Publication statusPublished - 2020


  • anti-tumor therapy
  • immunotherapy
  • inhibitory checkpoints
  • innate immunity
  • NK cells
  • HLA antigen class 1
  • interleukin 15
  • interleukin 2
  • natural killer cell receptor NKG2A
  • programmed death 1 receptor
  • cytotoxic T lymphocyte antigen 4
  • adoptive immunotherapy
  • cancer localization
  • cancer survival
  • cancer therapy
  • hematopoietic stem cell transplantation
  • human
  • in vivo study
  • leukemia
  • lymphocyte activation
  • lymphocyte proliferation
  • natural killer cell
  • nonhuman
  • protein expression
  • Review
  • animal
  • genetics
  • immunology
  • neoplasm
  • T lymphocyte
  • Animals
  • CTLA-4 Antigen
  • Histocompatibility Antigens Class I
  • Humans
  • Immunotherapy
  • Killer Cells, Natural
  • Neoplasms
  • T-Lymphocytes


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