RESUMEN
Natural killer (NK) cells are innate lymphocytes capable to recognize and kill virus-infected and cancer cells. In the past years, the use of allogeneic NK cells as anti-cancer therapy gained interest due to their ability to induce graft-versus-cancer responses without causing graft-versus-host disease and multiple protocols have been developed to produce high numbers of activated NK cells. While the ability of these cells to mediate tumor kill has been extensively studied, less is known about their capacity to influence the activity of other immune cells that may contribute to a concerted anti-tumor response in the tumor microenvironment (TME). In this study, we analyzed how an allogeneic off-the-shelf cord blood stem cell-derived NK-cell product influenced the activation of dendritic cells (DC). Crosstalk between NK cells and healthy donor monocyte-derived DC (MoDC) resulted in the release of IFNγ and TNF, MoDC activation, and the release of the T-cell-recruiting chemokines CXCL9 and CXCL10. Moreover, in the presence of prostaglandin-E2, NK cell/MoDC crosstalk antagonized the detrimental effect of IL-10 on MoDC maturation leading to higher expression of multiple (co-)stimulatory markers. The NK cells also induced activation of conventional DC2 (cDC2) and CD8+ T cells, and the release of TNF, GM-CSF, and CXCL9/10 in peripheral blood mononuclear cells of patients with metastatic colorectal cancer. The activated phenotype of MoDC/cDC2 and the increased release of pro-inflammatory cytokines and T-cell-recruiting chemokines resulting from NK cell/DC crosstalk should contribute to a more inflamed TME and may thus enhance the efficacy of T-cell-based therapies.
RESUMEN
Natural killer (NK) cells are increasingly used in clinical studies in order to treat patients with various malignancies. The following review summarizes platform lectures and 2013-2015 consortium meetings on manufacturing and clinical use of NK cells in Europe and United States. A broad overview of recent pre-clinical and clinical results in NK cell therapies is provided based on unstimulated, cytokine-activated, as well as genetically engineered NK cells using chimeric antigen receptors (CAR). Differences in donor selection, manufacturing and quality control of NK cells for cancer immunotherapies are described and basic recommendations are outlined for harmonization in future NK cell studies.
RESUMEN
OBJECTIVES: Natural killer cell receptors (NKR) have been implicated in rheumatoid (RA) and psoriatic arthritis (PsA) pathogenesis. To gain more insight into their role, we characterised NKR (co-)expression patterns on NK and T cells and NK cell function in RA and PsA. METHODS: The frequency of NK and T cells expressing killer like immunoglobulin (KIR) and NKG2 receptors and natural cytotoxicity receptors was assessed by 10-colour flow cytometry in peripheral blood of 23 RA, 12 PsA patients and 18 healthy donors (HD). NK cell cytotoxicity and IFN-gamma production was assessed in 8 RA patients and 8 HD. RESULTS: In RA but not PsA, the frequency of NK cells (median; range) expressing NKG2A (42%; 14-81%) was elevated compared to HD (23%; 9-58%). NKG2A⺠NK cells predominantly lack KIR, but display normal cytotoxicity and IFN-γ production. In contrast, RA patients with normal NKG2A⺠NK cell frequency have less functional NK cells compared to HD. T cells expressing Fc-gamma receptor CD16 were elevated in RA (median 0.75%) versus HD (0.3%). Furthermore, T cells expressing the KIRs CD158ah in both RA (0.7%) and PsA (0.3%), and CD158e1e2 in RA (1.5%) were elevated compared to HD (0.2% and 0.4%, respectively). In RA, CD4⺠T cells expressing the KIRs CD158ah, CD158b1b2j and CD158e1e2 were low (<2%) but significantly elevated compared to HD. CONCLUSIONS: This study demonstrates the presence of an elevated, functionally active NKG2A⺠KIR- NK cell population in RA. Together with an elevated frequency of NKR-expressing T cells, these changes may reflect differential pathogenetic involvement.
