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Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias

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Abstract

It is well established that natural killer (NK) cells play an important role in the immunity against cancer, while the involvement of other recently identified, NK-related innate lymphoid cells is still poorly defined. In the haploidentical hematopoietic stem cell transplantation for the therapy of high-risk leukemias, NK cells have been shown to exert a key role in killing leukemic blasts residual after conditioning. While the clinical results in the cure of leukemias are excellent, the exploitation of NK cells in the therapy of solid tumors is still limited and unsatisfactory. In solid tumors, NK cell function may be inhibited via different mechanisms, occurring primarily at the tumor site. The cellular interactions in the tumor microenvironment involve tumor cells, stromal cells and resident or recruited leukocytes and may favor tumor evasion from the host’s defenses. In this context, a number of cytokines, growth factors and enzymes synthesized by tumor cells, stromal cells, suppressive/regulatory myeloid and lymphoid cells may substantially impair the function of different tumor-reactive effector cells, including NK cells. The identification and characterization of such mechanisms may offer clues for the development of new immunotherapeutic strategies to restore effective anti-tumor responses. In order to harness NK cell-based immunotherapies, several approaches have been proposed, including reinforcement of NK cell cytotoxicity by means of specific cytokines, antibodies or drugs. These new tools may improve NK cell function and/or increase tumor susceptibility to NK-mediated killing. Hence, the integration of NK-based immunotherapies with conventional anti-tumor therapies may increase chances of successful cancer treatment.

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Abbreviations

ACT:

Adoptive cell transfer

ADCC:

Antibody-dependent cell-mediated cytotoxicity

ALL:

Acute lymphoblastic leukemia

AML:

Acute myeloid leukemia

BAT3/BAG6:

HLA-B-associated transcript 3/BCL2-associated athanogene 6

BM:

Bone marrow

CAR:

Chimeric antigen receptors

DNAM-1:

DNAX accessory molecule-1

EBV:

Epstein–barr virus

ELS:

Ectopic lymphoid structures

GvHD:

Graft-versus-host disease

GvL:

Graft-versus-leukemia

HCC:

Hepatocellular carcinoma

HSC:

Hematopoietic stem cell

HSCT:

Hematopoietic stem cell transplant

HSP-90:

Heat-shock protein 90

IDO:

Indoleamine 2,3-dioxygenase

IFN-γ:

Interferon-γ

IL:

Interleukin

ILC:

Innate lymphoid cells

KIRs:

Killer cell Ig-like receptors

LAK:

Lymphokine-activated killer

LSC:

Leukemic stem cells

LTi:

Lymphoid tissue inducer

mAbs:

Monoclonal antibodies

MDSC:

Myeloid-derived suppressor cells

MICA:

MHC class I chain-related gene A

MIF:

Migration inhibitory factor

MSC:

Mesenchymal stem cells

MUC16:

Mucin 16

NIMA:

Non-inherited maternal antigen

NK:

Natural killer

NKG2D:

Natural killer group 2, member D

PB:

Peripheral blood

PCNA:

Proliferating cell nuclear antigen

PE-NK cells:

Pleural effusions

PGE2:

Prostaglandin E2

PS:

Phosphatidylserine

SLOs:

Secondary lymphoid organs

TAF:

Tumor-associated fibroblasts

TAM:

Tumor-associated macrophages

TGF-β:

Transforming growth factor-β

TNF-α:

Tumor necrosis factor-α

TRAIL:

TNF-related apoptosis-inducing ligand

Tregs:

Regulatory T cells

VPA:

Sodium valproate

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Acknowledgments

This work was supported by Grants awarded by Associazione Italiana Ricerca sul Cancro (AIRC): IG 2010 project n. 10225 (to L. Moretta), IG 2014 project n. 15283 (to L. Moretta) and “Special Program Molecular Clinical Oncology 5 × 1000” project n. 9962 (to L. Moretta). This work was also supported by Italian Ministry of Health Grants RF-2010-2316606 (to F. Locatelli, L. Moretta and D. Pende) and RF-2010-2316319 (to D. Pende).

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Authors and Affiliations

  1. IRCCS AOU San Martino-IST, Genoa, Italy

    Gabriella Pietra, Chiara Vitale, Daniela Pende & Maria Cristina Mingari

  2. Department of Experimental Medicine, University of Genova, Genoa, Italy

    Gabriella Pietra, Chiara Vitale, Paola Vacca, Claudia Cantoni, Maria Cristina Mingari & Alessandro Moretta

  3. IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy

    Alice Bertaina, Franco Locatelli & Lorenzo Moretta

  4. Department of Medicine, University of Verona, Verona, Italy

    Francesca Moretta

  5. Ospedale Sacro Cuore, Negrar, Verona, Italy

    Francesca Moretta

  6. Istituto Giannina Gaslini, Via G. Gaslini n. 5, 16147, Genoa, Italy

    Michela Falco, Elisa Montaldo & Claudia Cantoni

  7. Center of Excellence for Biomedical Research, University of Genova, Genoa, Italy

    Claudia Cantoni, Maria Cristina Mingari & Alessandro Moretta

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  1. Gabriella Pietra
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  2. Chiara Vitale
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  3. Daniela Pende
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  4. Alice Bertaina
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  11. Alessandro Moretta
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  12. Franco Locatelli
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  13. Lorenzo Moretta
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Correspondence to Lorenzo Moretta.

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This article is part of the Symposium-in-Writing “Natural killer cells, ageing and cancer”, a series of papers published in Cancer Immunology, Immunotherapy.

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Pietra, G., Vitale, C., Pende, D. et al. Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias. Cancer Immunol Immunother 65, 465–476 (2016). https://doi.org/10.1007/s00262-015-1744-y

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