Abstract
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 language | English |
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Journal | Front. Immunol. |
Volume | 10 |
DOIs | |
Publication status | Published - 2020 |
Keywords
- 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