PMN-MDSC are a new target to rescue graft-versus-leukemia activity of NK cells in haplo-HSC transplantation

Tumino, Nicola; Besi, Francesca; Pace, Anna; Mariotti, Francesca Romana; Merli, Pietro; Pira, Giuseppina Li; Galaverna, Federica; Pitisci, Angela; Ingegnere, Tiziano; Pelosi, Andrea; Quatrini, Linda; Munari, Enrico; Locatelli, Franco; Moretta, Alessandro; Vacca, Paola

doi:10.1038/s41375-019-0585-7

Cited by 33 publications

(36 citation statements)

References 15 publications

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“…Although NK cells are capable of a potent cytotoxicity against cancer cells, their activity is frequently impaired by tumor cells and by TME, including cells either resident or recruited, and may be polarized by signals delivered primarily by M2 macrophages, myeloid-derived suppressor cells (MDSC), and T regulatory (Treg) cells [6,7]. In this context, cell-to-cell communication by direct contact and/or exchange of soluble mediators represents a major mechanism involved in the modulatory activity of TME, resulting in promotion of tumor growth and inhibition of immune response [8,9].…”

Section: Introductionmentioning

confidence: 99%

Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor

Pace

Tumino

Besi

et al. 2020

Cancers

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113

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Despite the pivotal role of natural killer (NK) cells in defenses against tumors, their exploitation in cancer treatment is still limited due to their reduced ability to reaching tumor sites and the inhibitory effects of tumor microenvironment (TME) on their function. In this study, we have characterized the exosomes from IL2- or IL15-cultured human NK cells. Both cytokines induced comparable amounts of exosomes with similar cargo composition. Analysis of molecules contained within or exposed at the exosome surface, allowed the identification of molecules playing important roles in the NK cell function including IFN-γ, Lymphocyte Function-Associated Antigen (LFA-1), DNAX Accessory Molecule-1 (DNAM1) and Programmed Cell Death Protein (PD-1). Importantly, we show that DNAM1 is involved in exosome-mediated cytotoxicity as revealed by experiments using blocking antibodies to DNAM1 or DNAM1 ligands. In addition, antibody-mediated inhibition of exosome cytotoxicity results in a delay in target cell apoptosis. We also provide evidence that NK-exosomes may exert their cytolytic activity after short time interval and even at low concentrations. Regarding their possible use in immunotherapy, NK exosomes, detectable in peripheral blood, can diffuse into tissues and exert their cytolytic effect at tumor sites. This property offers a clue to integrate cancer treatments with NK exosomes.

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Section: Introductionmentioning

confidence: 99%

Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor

Pace

Tumino

Besi

et al. 2020

Cancers

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113

132

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“…Nevertheless, they may indirectly influence the anti-leukemia activity of the other immune cells present in the graft by releasing cytokines. For example, ILC2s may activate a tolerogenic pathway and favor MDSC-dependent suppression of NK function (49), analogously to what was shown in APL (28). Moreover, like NK cells, through cytokine secretion, hILCs may play an important role in the protection against infections during the early time window following HSCT, when the donor-derived immune system is not yet reconstituted.…”

Section: Allogenic Hsct To Treat Hematological Malignanciesmentioning

confidence: 76%

Helper Innate Lymphoid Cells in Allogenic Hematopoietic Stem Cell Transplantation and Graft Versus Host Disease

et al. 2020

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Helper Innate Lymphoid Cells (hILCs), including ILC1s, ILC2s, and ILC3s, are mainly localized at the mucosal barriers where they play an important role in tissue regeneration and homeostasis through the secretion of specific sets of cytokines. The recent identification of a circulating ILC precursor able to generate all ILC mature subsets in physiological conditions, suggests that "ILC-poiesis" may be important in the context of hematopoietic stem cell transplantation (HSCT). Indeed, in HSCT the conditioning regimen (chemotherapy and radiotherapy) and Graft vs Host Disease (GvHD) may cause severe damages to mucosal tissues. Therefore, it is conceivable that rapid reconstitution of the hILC compartment may be beneficial in HSCT, by promoting mucosal tissue repair/regeneration and providing protection from opportunistic infections. In this review, we will summarize the evidence for a role of hILCs in allogenic HSCT for the treatment of hematological malignancies in all its steps, from the preparative regimen to the immune reconstitution in the recipient. The protective properties of hILCs at the mucosal barrier interfaces make them an attractive target to exploit in future cellular therapies aimed at improving allogenic HSCT outcome.

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“…However, no significant influence on NK cell reconstitution has been observed [59] in this latter group. A further attempt to optimize graft engineering in the haploidentical setting might include the depletion of CD66b + polymorphonuclear myeloid derived suppressor cells (PMN-MDSC), which were recently demonstrated to exert an inhibitory effect on NK cells [60]. Finally, the donor selection criteria can be continuously refined, following the increased knowledge on NK-cell mediated GvL effect, as well as on specific features correlating with better clinical outcome in transplanted patients.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia

Meazza

Falco

Loiacono

et al. 2020

Cancers

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NK cells can exert remarkable graft-versus-leukemia (GvL) effect in HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Here, we dissected the NK-cell repertoire of 80 pediatric acute leukemia patients previously reported to have an excellent clinical outcome after αβT/B-depleted haplo-HSCT. This graft manipulation strategy allows the co-infusion of mature immune cells, mainly NK and γδT cells, and hematopoietic stem cells (HSCs). To promote NK-cell based antileukemia activity, 36/80 patients were transplanted with an NK alloreactive donor, defined according to the KIR/KIR-Ligand mismatch in the graft-versus-host direction. The analysis of the reconstituted NK-cell repertoire in these patients showed relatively high proportions of mature and functional KIR+NKG2A−CD57+ NK cells, including the alloreactive NK cell subset, one month after HSCT. Thus, the NK cells adoptively transfused with the graft persist as a mature source of effector cells while new NK cells differentiate from the donor HSCs. Notably, the alloreactive NK cell subset was endowed with the highest anti-leukemia activity and its size in the reconstituted repertoire could be influenced by human cytomegalovirus (HCMV) reactivation. While the phenotypic pattern of donor NK cells did not impact on post-transplant HCMV reactivation, in the recipients, HCMV infection/reactivation fostered a more differentiated NK-cell phenotype. In this cohort, no significant correlation between differentiated NK cells and relapse-free survival was observed.

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PMN-MDSC are a new target to rescue graft-versus-leukemia activity of NK cells in haplo-HSC transplantation

Cited by 33 publications

References 15 publications

Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor

Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor

Helper Innate Lymphoid Cells in Allogenic Hematopoietic Stem Cell Transplantation and Graft Versus Host Disease

Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia

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