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Allogeneic natural killer (NK) cell therapy has been effective in treating cancer. Many studies have tested NK cell therapy using human pluripotent stem cells (hPSCs). However, the impacts of the origin of PSC-NK cells on competence are unclear. In this study, several types of hPSCs, including human-induced PSCs (hiPSCs) generated from CD34+, CD3−CD56+, and CD56− cells in umbilical cord blood (UCB), three lines of human embryonic stem cells (hESCs, ES-1. ES-2 and ES-3) and MHC I knockout (B2M-KO)-ESCs were used to differentiate into NK cells and their capacities were analyzed. All PSC types could differentiate into NK cells. Among the iPSC-derived NK cells (iPSC-NKs) and ESC-derived NK cells (ES-NKs), 34+ iPSCs and ES-3 had a higher growth rate and cytotoxicity, respectively, ES-3 also showed better efficacy than 34+ iPSCs. B2M-KO was similar to the wild type. These results suggest that the screening for differentiation of PSCs into NK cells prior to selecting the PSC lines for the development of NK cell immunotherapy is an essential process for universal allotransplantation, including the chimeric antigen receptor (CAR). [ABSTRACT FROM AUTHOR]

Allogeneic natural killer (NK) cell therapy has been effective in treating cancer. Many studies have tested NK cell therapy using human pluripotent stem cells (hPSCs). However, the impacts of the origin of PSC-NK cells on competence are unclear. In this study, several types of hPSCs, including human-induced PSCs (hiPSCs) generated from CD34+, CD3−CD56+, and CD56− cells in umbilical cord blood (UCB), three lines of human embryonic stem cells (hESCs, ES-1. ES-2 and ES-3) and MHC I knockout (B2M-KO)-ESCs were used to differentiate into NK cells and their capacities were analyzed. All PSC types could differentiate into NK cells. Among the iPSC-derived NK cells (iPSC-NKs) and ESC-derived NK cells (ES-NKs), 34+ iPSCs and ES-3 had a higher growth rate and cytotoxicity, respectively, ES-3 also showed better efficacy than 34+ iPSCs. B2M-KO was similar to the wild type. These results suggest that the screening for differentiation of PSCs into NK cells prior to selecting the PSC lines for the development of NK cell immunotherapy is an essential process for universal allotransplantation, including the chimeric antigen receptor (CAR).

The differentiation of human induced pluripotent stem cells (hiPSCs) into T and natural killer (NK) lymphocytes opens novel possibilities for developmental studies of immune cells and in-vitro generation of cell therapy products. In particular, iPSC-derived NK cells gained interest in adoptive anti-cancer immunotherapies, since they enable generation of homogenous populations of NK cells with and without genetic engineering that can be grown at clinical scale. However, the phenotype of in-vitro generated NK cells is not well characterized. NK cells derive in the bone marrow and mature in secondary lymphoid tissues through distinct stages from CD56brightCD16- to CD56dimCD16+ NK cells that represents the most abandoned population in peripheral blood. In this study, we efficiently generated CD56+CD16+CD3- NK lymphocytes from hiPSC and characterized NK-cell development by surface expression of NK-lineage markers. Hematopoietic priming of hiPSC resulted in 31.9% to 57.4% CD34+CD45+ hematopoietic progenitor cells (HPC) that did not require enrichment for NK lymphocyte propagation. HPC were further differentiated into NK cells on OP9-DL1 feeder cells resulting in high purity of CD56brightCD16- and CD56brightCD16+ NK cells. The output of generated NK cells increased up to 40% when OP9-DL1 feeder cells were inactivated with mitomycine C. CD7 expression could be detected from the first week of differentiation indicating priming towards the lymphoid lineage. CD56brightCD16-/+ NK cells expressed high levels of DNAM-1, CD69, natural killer cell receptors NKG2A and NKG2D, and natural cytotoxicity receptors NKp46, NKp44, NKp30. Expression of NKp80 on 40% of NK cells, and a perforin+ and granzyme B+ phenotype confirmed differentiation up to stage 4b. Killer cell immunoglobulin-like receptor KIR2DL2/DL3 and KIR3DL1 were found on up to 3 and 10% of mature NK cells, respectively. NK cells were functional in terms of cytotoxicity, degranulation and antibody-dependent cell-mediated cytotoxicity.

The differentiation of human induced pluripotent stem cells (hiPSCs) into T and natural killer (NK) lymphocytes opens novel possibilities for developmental studies of immune cells and in-vitro generation of cell therapy products. In particular, iPSC-derived NK cells gained interest in adoptive anti-cancer immunotherapies, since they enable generation of homogenous populations of NK cells with and without genetic engineering that can be grown at clinical scale. However, the phenotype of in-vitro generated NK cells is not well characterized. NK cells derive in the bone marrow and mature in secondary lymphoid tissues through distinct stages from CD56brightCD16- to CD56dimCD16+ NK cells that represents the most abandoned population in peripheral blood. In this study, we efficiently generated CD56+CD16+CD3- NK lymphocytes from hiPSC and characterized NK-cell development by surface expression of NK-lineage markers. Hematopoietic priming of hiPSC resulted in 31.9% to 57.4% CD34+CD45+ hematopoietic progenitor cells (HPC) that did not require enrichment for NK lymphocyte propagation. HPC were further differentiated into NK cells on OP9-DL1 feeder cells resulting in high purity of CD56brightCD16- and CD56brightCD16+ NK cells. The output of generated NK cells increased up to 40% when OP9-DL1 feeder cells were inactivated with mitomycine C. CD7 expression could be detected from the first week of differentiation indicating priming towards the lymphoid lineage. CD56brightCD16-/+ NK cells expressed high levels of DNAM-1, CD69, natural killer cell receptors NKG2A and NKG2D, and natural cytotoxicity receptors NKp46, NKp44, NKp30. Expression of NKp80 on 40% of NK cells, and a perforin+ and granzyme B+ phenotype confirmed differentiation up to stage 4b. Killer cell immunoglobulin-like receptor KIR2DL2/DL3 and KIR3DL1 were found on up to 3 and 10% of mature NK cells, respectively. NK cells were functional in terms of cytotoxicity, degranulation and antibody-dependent cell-mediated cytotoxicity. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells have a central role within the innate immune system, eliminating virally infected, foreign and transformed cells through their natural cytotoxic capacity. Release of their cytotoxic granules is tightly controlled through the balance of a large repertoire of inhibitory and activating receptors, and it is the unique combination of these receptors expressed by individual cells that confers immense diversity both in phenotype and functionality. The diverse, yet unique, NK cell repertoire within an individual is surprisingly stable over time considering the constant renewal of these cells at steady state. Here we give an overview of NK cell differentiation and discuss metabolic requirements, intra-lineage plasticity and transcriptional reprogramming during IL-15-driven homeostatic proliferation. New insights into the regulation of NK cell differentiation and homeostasis could pave the way for the successful implementation of NK cell-based immunotherapy against cancer.

NK cells, which are composed of phenotypically and functionally heterogeneous subpopulations, play critical roles in immunity against cancer. The mechanism of generation of distinct subsets such as the effector and regulatory subtypes is unclear. Here, we show that this process comprises several steps, including generation of proliferating, highly cytotoxic cells activated by IL-15/IL-18 and differentiation into distinct cell populations induced with IL-12. Freshly prepared murine splenic NK cells expressed IL-15Rs and IL-18Rs and rapidly began to proliferate following stimulation with IL-15/IL-18. The proliferating NK cells highly expressed various activation markers such as B220, CD49b (DX5), lysosome-associated membrane glycoprotein 1 (LAMP-1), DNAX accessory molecule 1, perforin, and granzyme B and showed reduced expression of natural killer cell p46-related protein (NKp46) and IL-18Rα. These cells exerted strong cytotoxicity against YAC-1 cells, but did not secrete cytokines. IL-12 rapidly activated STAT4 in these cells, induced IFN-γ production, and then upregulated p21 and p27, leading to withdrawal from the cell cycle. In parallel, IL-12-stimulated cells gradually reduced cytotoxicity, decreased expression of activation markers, and instead increased expression of Sca-1, CD25, CD49a, and NKp46. Some IL-15/IL-18-induced cells strongly expressed PD-1, whereas NK cells induced with IL-15/IL-18 and IL-12 expressed high levels of T cell immunoglobulin mucin-3, LAG-3, and natural killer group 2 A. Furthermore, these cells spontaneously secreted IL-10 and TGF-β following prolonged incubation. Thus, IL-12 regulates expansion of NK cells activated with IL-15/IL-18, influences the population size of highly cytotoxic cells, and induces differentiation to unique cells sharing some phenotypes of ILCs. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells have a central role within the innate immune system, eliminating virally infected, foreign and transformed cells through their natural cytotoxic capacity. Release of their cytotoxic granules is tightly controlled through the balance of a large repertoire of inhibitory and activating receptors, and it is the unique combination of these receptors expressed by individual cells that confers immense diversity both in phenotype and functionality. The diverse, yet unique, NK cell repertoire within an individual is surprisingly stable over time considering the constant renewal of these cells at steady state. Here we give an overview of NK cell differentiation and discuss metabolic requirements, intra-lineage plasticity and transcriptional reprogramming during IL-15-driven homeostatic proliferation. New insights into the regulation of NK cell differentiation and homeostasis could pave the way for the successful implementation of NK cell-based immunotherapy against cancer. [ABSTRACT FROM AUTHOR]

Abstract: T‐bet and Eomes are T‐box transcription factors that drive the differentiation and function of cytotoxic lymphocytes such as NK cells. Their DNA‐binding domains are highly similar, suggesting redundant transcriptional activity. However, while these transcription factors have different patterns of expression, the phenotype of loss‐of‐function mouse models suggests that they play distinct roles in the development of NK cells and other innate lymphoid cells (ILCs). Recent technological advances using reporter mice and conditional knockouts were fundamental in defining the regulation and function of these factors at steady state and during pathological conditions such as various types of cancer or infection. Here, we review these recent developments, focusing on NK cells as prototypical cytotoxic lymphocytes and their development, and also discuss parallels between NK cells and T cells. We also examine the role of T‐bet and Eomes in human NK cells and ILC1s. Considering divergent findings on mouse and human ILC1s, we propose that NK cells are defined by coexpression of T‐bet and Eomes, while ILC1s express only one of these factors, either T‐bet or Eomes, depending on the tissue or the species. [ABSTRACT FROM AUTHOR]

Immunotherapy, via intra-vesical instillations of BCG, is the therapy of choice for patients with high-risk non-muscle invasive bladder cancer. The subsequent recruitment of lymphocytes and myeloid cells, as well as the release of cytokines and chemokines, is believed to induce a local immune response that eliminates these tumors, but the detailed mechanisms of action of this therapy are not well understood. Here, we have studied the phenotype and function of the responding lymphocyte populations as well as the spectrum of cytokines and chemokines produced in an in vitro model of human peripheral blood mononuclear cells (PBMCs) co-cultured with BCG. Natural killer (NK) cell activation was a prominent feature of this immune response and we have studied the expansion of this lymphocyte population in detail. We show that, after BCG stimulation, CD56dim NK cells proliferate, upregulate CD56, but maintain the expression of CD16 and the ability to mediate ADCC. CD56bright NK cells also contribute to this expansion by increasing CD16 and KIR expression. These unconventional CD56bright cells efficiently degranulated against bladder cancer cells and the expansion of this population required the release of soluble factors by other immune cells in the context of BCG. Consistent with these in vitro data, a small, but significant increase in the intensity of CD16 expression was noted in peripheral blood CD56bright cells from bladder cancer patients undergoing BCG therapy, that was not observed in patients treated with mitomycin-C instillations. These observations suggest that activation of NK cells may be an important component of the anti-tumoral immune response triggered by BCG therapy in bladder cancer.

Natural killer cells (NK cells) are traditionally attributed to the innate immune system. It is considered that previously received stimuli have little effect on the functioning of these immune cells. Indeed, NK cells even without prior sensitization provide a rapid effector response against tumor, virus-infected, or otherwise damaged cells. They have a limited repertoire of receptors, the expression of which does not require somatic recombination. However, recent data indicate that NK cells may acquire the properties specific to adaptive immune cells. In particular, NK cells have been shown to possess the features of immunological memory, namely, the ability to more quickly and effectively respond to a repeated stimulus. The mechanisms of memory acquisition in NK cells differ from those implemented in T and B lymphocytes and are still rather vague. Presumably, some of these mechanisms underlie the significant phenotypic and functional NK cell diversity emerging during their differentiation. The recent data accumulated in this area considerably change the existing immunology paradigm, which postulates a clear delineation of the adaptive and innate immune cells. The published data on phenotypic and functional characteristics of NK cells and particular changes in these characteristics during NK cell differentiation and generation of memory-like NK cells are reviewed. [ABSTRACT FROM AUTHOR]

The interest in innate lymphoid cells (ILC) has rapidly grown during the last decade. ILC include distinct cell types that are collectively involved in host protection against pathogens and tumor cells and in the regulation of tissue homeostasis. Studies in mice enabled a broad characterization of ILC function and of their developmental requirements. In humans all mature ILC subsets have been characterized and their role in the pathogenesis of certain disease is emerging. Nonetheless, still limited information is available on human ILC development. Indeed, only the cell precursors committed toward NK cells or ILC3 have been described. Here, we review the most recent finding on human mature ILC, discussing their tissue localization and function. Moreover, we summarize the available data regarding human ILC development. [ABSTRACT FROM AUTHOR]

Abstract: The study of in vitro and in vivo NK cell differentiation from hematopoietic precursors revealed the existence of discrete stages of development. These stages are characterized by the progressive acquisition of markers and receptors that play a crucial role in NK cell function. The knowledge acquired has revealed particularly relevant for improving the HSCT to cure high-risk leukemias in the haplo-HSCT setting, in which NK cells play a central role in the clearance of leukemic cells and in the positive clinical outcome. [Copyright &y& Elsevier]

Abstract: While conventional NK cells play an important role in early defenses against pathogens thanks to their cytolytic activity and production of pro-inflammatory chemokines and cytokines, those present in decidua (dNK cells), during early pregnancy, are primarily involved in tissue building and remodeling and in the formation of new blood vessels. This occurs mainly via the release of IL-8, VEGF, SDF-1 and IP-10. In addition, we show that by interacting with particular myelomonocytic cells (dCD14+) they contribute to the induction of regulatory T cells (Tregs). In turn, Tregs are thought to play a pivotal role in immunosuppression and induction of tolerance toward the fetal allograft. We recently demonstrated that CD34+ hematopoietic precursors (dCD34+) are present in decidual tissues, thus suggesting that dNK cells might derive from such precursors. Indeed, this was confined by in vitro experiments in which dCD34+ cells differentiated into dNK cells upon culture with appropriate cytokine combinations or even in co-culture with decidua-derived stromal cells (dSC). It is possible to speculate that inappropriate cellular interactions in the decidual microenvironment or defects of dNK (or dCD14+) cell generation might negatively influence pregnancy success. [Copyright &y& Elsevier]

Gene expression can be modulated depending on physiological and developmental requirements. A multitude of regulatory genes, which are organized in interdependent networks, guide development and eventually generate specific phenotypes. Transcription factors (TF) are a key element in the regulatory cascade controlling cell fate and effector functions. In this review, we discuss recent data on the diversity of TF that determine natural killer (NK) cell fate and NK cell function. [ABSTRACT FROM AUTHOR]

Abstract: Patients undergoing allogeneic bone marrow transplantation (BMT) offer a unique system to analyze the NK cell development in vivo. We analyzed NK cells from 24 such patients to assess the acquisition of activating receptors. Five patients displayed an immature NK cell surface phenotype at engraftment, as they were CD16-, KIRs- and NKG2D- while expressed low levels of NKp46, NKp30, 2B4 and NKG2A. These NK cells had particularly low cytolytic activity against the HLA-class I-negative melanoma F01 cell line and the 721.221 Epstein-Barr virus (EBV)B-infected cells. Moreover, cytoxicity was inhibited upon mAb-mediated crosslinking of 2B4. Analysis of NK cells at day 30 after BMT revealed the occurrence of both phenotypic and functional maturation. These data are in agreement with a previous in vitro study showing that immature NK cell precursors express CD16, NKGD2 and killer Ig-like receptors (KIR) only at a late stage of differentiation and also express inhibitory 2B4. Remarkably, one of these patients did not display any phenotypic and functional maturation of NK cells and experienced a fatal post transplant EBV-related lymphoproliferative disease. Our present study allows a better understanding of the NK cell differentiation in vivo. [Copyright &y& Elsevier]

Cultured blood CD34+ progenitors from patients with myeloid metaplasia with myelofibrosis (MMM) failed to differentiate into natural killer (NK) cells with recombinant interleukin (IL)-15. No NK cells either could be induced in coculture with IL-15-expressing fibroblasts from MMM patients’ spleens. The impaired NK differentiation could be circumvented by using normal blood CD34+ cells in the coculture. In this case, cell-to-cell contact and IL-15 interaction were crucial for NK cell differentiation. Pretreatment of normal CD34+ progenitors with anti-IL-15 monoclonal antibody markedly reduced NK cell production while MMM fibroblast pretreatment did not. Both normal and MMM progenitors constitutively expressed IL-15. Analysis of endogenous IL-15 signaling pathway revealed a constitutive γc/Jak3 association and STAT3 activation in the two types of progenitors. Anti-IL-15 monoclonal antibody treatment caused a downregulation of IL-15 signaling in normal but not MMM blood cells. The impaired NK differentiation in MMM may thus arise from a deregulated control of an endogenous IL-15 involved in hematopoietic progenitors’ lymphoid differentiation. [Copyright &y& Elsevier]

Natural killer (NK) cells are lymphocytes that play an important role at clearing virally infected or cancer cells. Their potential and role in cancer immunotherapy have generated great interest, given the promising results of NK cell adoptive transfer clinical trials. The remaining challenge to bring emerging NK cell immunotherapies to the clinic is to enhance the production of large numbers of functionally competent NK cells ex vivo. Here, we describe two in vitro NK cell development assays using hematopoietic progenitor cells (HPCs), one for human NK cells and one for mouse NK cells. These protocols describe two robust methods that can be utilized for investigation of NK cell development and function., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

• Developmental events of NK cells are regulated through multiple critical cytokines, transcription factors, and MicroRNAs. • The interleukins such as, IL-2, IL-3, IL-7, IL-15, IL-21 etc. have key roles in NK cell development. • The MicroRNAs such as miR-132, miR-212, and miR-200a are involved in NK cell development and differentiation. NK cells are innate immune cells derived from common lymphoid progenitor and are developed primarily in the bone marrow. These cells respond to stress signals, inflammatory cytokines, and cancerous cells through the secretion of active immune mediators. Previous studies revealed that NK cells can be used as an essential cell in the defense against cancers. According to the literature, a set of cytokines and factors play a crucial role during differentiation of NK cells. In other words, developmental events of NK cells are regulated through multiple critical cytokines, including interleukins (ILs), kit ligand, fms-like tyrosine kinase three ligand, transforming growth factor-β, and typical γ chain family of cytokines. Among previously investigated ILs, IL-2, IL-3, IL-7, and IL-15 are the most important. In addition to ILs, transcription factors and MicroRNAs are involved in NK cell development. In this review study, after presenting a brief description of developmental stages and production of the NK cells, the factors and signaling pathways involved in differentiation of NK cells were discussed. [ABSTRACT FROM AUTHOR]

To investigate the effects of lead on human immune system, we analyzed T cell subpopulations (CD4+, CD8+ and CD3+ cells), natural killer (NK) cell subpopulations (CD16+ and CD57+ cells) and B (CD19+) cells in peripheral blood in 29 male lead workers. All were engaged in manufacturing lead stearate in a chemical factory. They were aged 23–74 (mean 49) years. Their blood lead concentrations (PbB) were between 7 and 35 (mean 18) μg/dl. They were divided into two groups according to their PbB: a high-PbB group (?20 μg/dl), and a low-PbB group (<20 μg/dl). The control group consisted of 19 “healthy” male workers without a history of occupational exposure to lead or to other hazardous substances, aged 48–67 (mean 58) years. The number and percentage of CD16+ cells in the high-PbB group were significantly lower than those in the controls and in the low-PbB group. There was significant negative correlation between the number of CD16+ cells and PbB in the lead workers. The percentage of CD8+ cells in the high-PbB group was larger than that in the controls and in the low-PbB group. It is suggested that the CD16+ NK cell should be a major site of the effects of lead on lymphocyte subpopulations. [ABSTRACT FROM AUTHOR]

The differentiation of human induced pluripotent stem cells (hiPSCs) into T and natural killer (NK) lymphocytes opens novel possibilities for developmental studies of immune cells and in-vitro generation of cell therapy products. In particular, iPSC-derived NK cells gained interest in adoptive anti-cancer immunotherapies, since they enable generation of homogenous populations of NK cells with and without genetic engineering that can be grown at clinical scale. However, the phenotype of in-vitro generated NK cells is not well characterized. NK cells derive in the bone marrow and mature in secondary lymphoid tissues through distinct stages from CD56 bright CD16 - to CD56 dim CD16 + NK cells that represents the most abandoned population in peripheral blood. In this study, we efficiently generated CD56 + CD16 + CD3 - NK lymphocytes from hiPSC and characterized NK-cell development by surface expression of NK-lineage markers. Hematopoietic priming of hiPSC resulted in 31.9% to 57.4% CD34 + CD45 + hematopoietic progenitor cells (HPC) that did not require enrichment for NK lymphocyte propagation. HPC were further differentiated into NK cells on OP9-DL1 feeder cells resulting in high purity of CD56 bright CD16 - and CD56 bright CD16 + NK cells. The output of generated NK cells increased up to 40% when OP9-DL1 feeder cells were inactivated with mitomycine C. CD7 expression could be detected from the first week of differentiation indicating priming towards the lymphoid lineage. CD56 bright CD16 -/+ NK cells expressed high levels of DNAM-1, CD69, natural killer cell receptors NKG2A and NKG2D, and natural cytotoxicity receptors NKp46, NKp44, NKp30. Expression of NKp80 on 40% of NK cells, and a perforin + and granzyme B + phenotype confirmed differentiation up to stage 4b. Killer cell immunoglobulin-like receptor KIR2DL2/DL3 and KIR3DL1 were found on up to 3 and 10% of mature NK cells, respectively. NK cells were functional in terms of cytotoxicity, degranulation and antibody-dependent cell-mediated cytotoxicity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Euchner, Sprissler, Cathomen, Fürst, Schrezenmeier, Debatin, Schwarz and Felgentreff.)

A population of uterine natural killer (NK) cells, commonly called granulated metrial gland (GMG) cells, differentiates in the mouse uterus during normal pregnancy. Little is known regarding the process of differentiation of GMG cells or of other NK cell subsets. It has been suggested that macrophage precursors, under the combined influences of the cytokine growth factors colony stimulating factor-1 (CSF-1) and interleukin-2, become NK-cell like in morphology, pattern of target cell lysis and surface antigen phenotype. Mice expressing the mutation osteopetrosis ( op/op) are unable to produce the cytokine CSF-1. To determine whether CSF-1 is required for the successful differentiation of uterine NK cells, implantation sites in pregnant, op/op mice were studied histologically. GMG cell differentiation appeared to progress normally in op/op mice studied between days 7 and 14 of gestation. Thus, the growth factor CSF-1 is not required for differentiation of the uterine NK cell subset known as GMG cells and probably GMG cells do not differentiate from macrophage precursor cells which are deficient in op/op mice. [ABSTRACT FROM AUTHOR]

Immunotherapy, via intra-vesical instillations of BCG, is the therapy of choice for patients with high-risk non-muscle invasive bladder cancer. The subsequent recruitment of lymphocytes and myeloid cells, as well as the release of cytokines and chemokines, is believed to induce a local immune response that eliminates these tumors, but the detailed mechanisms of action of this therapy are not well understood. Here, we have studied the phenotype and function of the responding lymphocyte populations as well as the spectrum of cytokines and chemokines produced in anin vitromodel of human peripheral blood mononuclear cells (PBMCs) co-cultured with BCG. Natural killer (NK) cell activation was a prominent feature of this immune response and we have studied the expansion of this lymphocyte population in detail. We show that, after BCG stimulation, CD56dimNK cells proliferate, upregulate CD56, but maintain the expression of CD16 and the ability to mediate ADCC. CD56brightNK cells also contribute to this expansion by increasing CD16 and KIR expression. These unconventional CD56brightcells efficiently degranulated against bladder cancer cells and the expansion of this population required the release of soluble factors by other immune cells in the context of BCG. Consistent with thesein vitrodata, a small, but significant increase in the intensity of CD16 expression was noted in peripheral blood CD56brightcells from bladder cancer patients undergoing BCG therapy, that was not observed in patients treated with mitomycin-C instillations. These observations suggest that activation of NK cells may be an important component of the anti-tumoral immune response triggered by BCG therapy in bladder cancer. [ABSTRACT FROM AUTHOR]