AUTHOR=Vacca Paola , Pietra Gabriella , Tumino Nicola , Munari Enrico , Mingari Maria Cristina , Moretta Lorenzo 

TITLE=Exploiting Human NK Cells in Tumor Therapy

JOURNAL=Frontiers in Immunology

VOLUME=Volume 10 - 2019

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.03013

DOI=10.3389/fimmu.2019.03013

ISSN=1664-3224

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 in 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, CTLA4, 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.