NK cell maturation to CD56dim subset associated with high levels of NCRs overrides the inhibitory effect of NKG2A and recovers impaired NK cell cytolytic potential after allogeneic hematopoietic stem cell transplantation

Autologous hematopoietic stem cell transplantation (autoHSCT) is a standard of care for transplant-eligible patients with multiple myeloma (MM). Among factors that influence outcome after autoHSCT, it has been suggested that the number of natural killer (NK) cells plays an important role. However, the impact that different NK cell subsets and their phenotype could have in disease progression after autoHSCT are less clear. For this reason, we have phenotypically and functionally characterized NK cells during immune system reconstitution after autoHSCT in 54 MM patients. Shortly after leukocyte recovery, an extensive redistribution of NK cell subsets occurs in these patients. In addition, NK cells undergo a profound phenotypic change characterized, among others, by their increased proliferative capacity and immature phenotype. Importantly, MM patients who showed lower frequencies of the mature highly differentiated NKG2A-CD57+ NK cell subset at +30 and +100 days after autoHSCT experienced superior progression-free survival and had a longer time to the next treatment than those with higher frequencies. Our results provide significant insights into NK cell reconstitution after autoHSCT and suggest that the degree of NK cell maturation after autoHSCT affects the clinical outcome of MM patients treated with this therapeutic strategy.

Download Full-text

Human NK Cells in Autologous Hematopoietic Stem Cell Transplantation for Cancer Treatment

Cancers ◽

10.3390/cancers13071589 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1589

Author(s):

Ane Orrantia ◽

Iñigo Terrén ◽

Gabirel Astarloa-Pando ◽

Olatz Zenarruzabeitia ◽

Francisco Borrego

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Nk Cells ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Cell Biology ◽

Nk Cell ◽

Hematopoietic Stem ◽

Autologous Hsct

Natural killer (NK) cells are phenotypically and functionally diverse lymphocytes with the ability to recognize and kill malignant cells without prior sensitization, and therefore, they have a relevant role in tumor immunosurveillance. NK cells constitute the main lymphocyte subset in peripheral blood in the first week after hematopoietic stem cell transplantation (HSCT). Although the role that NK cells play in allogenic HSCT settings has been documented for years, their significance and beneficial effects associated with the outcome after autologous HSCT are less recognized. In this review, we have summarized fundamental aspects of NK cell biology, such as, NK cell subset diversity, their effector functions, and differentiation. Moreover, we have reviewed the factors that affect autologous HSCT outcome, with particular attention to the role played by NK cells and their receptor repertoire in this regard.

Download Full-text

Donor and host coexpressing KIR ligands promote NK education after allogeneic hematopoietic stem cell transplantation

Blood Advances ◽

10.1182/bloodadvances.2019000242 ◽

2019 ◽

Vol 3 (24) ◽

pp. 4312-4325 ◽

Cited By ~ 4

Author(s):

Xiang-Yu Zhao ◽

Xing-Xing Yu ◽

Zheng-Li Xu ◽

Xun-Hong Cao ◽

Ming-Rui Huo ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Nk Cells ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Nk Cell ◽

K562 Cells ◽

Inhibitory Receptors ◽

Hematopoietic Stem

Abstract The rate and extent of natural killer (NK)–cell education after hematopoietic cell transplantation correlates with leukemia control. To study the effect of donor and host HLA on NK-cell reconstitution, single killer-cell immunoglobulin-like receptor (KIR)+ NK cells (exhibiting KIR2DL1, KIR2DL2/KIR2DL3, or KIR3DL1 as their sole receptor) were grouped into 4 groups based on the interaction between donor/host HLA and donor inhibitory KIR in 2 cohorts (n = 114 and n = 276, respectively). On days 90 to 180 after transplantation, the absolute number and responsiveness against K562 cells (CD107a or interferon-γ expression) of single-KIR+ NK cells were higher in pairs where donor and host HLA both expressed ligands for donor inhibitory KIRs than in pairs where 1 or both of the donor and recipient HLA lacked at least 1 KIR ligand. NK-cell responsiveness was tuned commensurate with the number of inhibitory receptors from the donor. When both donor and host expressed the 3 major KIR ligands (HLA-C1, HLA-C2, and HLA-Bw4), NK cells expressing 3 inhibitory receptors (KIR2DL1/2DL3/3DL1) reached the maximum responsiveness against K562 cells compared with those NK cells expressing only 1 or 2 inhibitory receptors. When donor and host HLA both expressed all ligands for donor inhibitory KIRs, patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) showed the lowest recurrence rate after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). In conclusion, this study demonstrates that when both donors and hosts present all the KIR ligands for donor KIRs, reconstituted NK cells achieve better functional education and contribute to least relapse among patients. This observation study was registered at www.clinicaltrials.gov as #NCT02978274.

Download Full-text

IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation

Cancers ◽

10.3390/cancers12113189 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3189 ◽

Cited By ~ 1

Author(s):

Maite Alvarez ◽

Cordelia Dunai ◽

Lam T. Khuat ◽

Ethan G. Aguilar ◽

Isabel Barao ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Nk Cells ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Immune Cells ◽

Nk Cell ◽

Continuous Treatment ◽

Hematopoietic Stem

The failure of autologous hematopoietic stem cell transplantation (HSCT) has been associated with a profound immunodeficiency that follows shortly after treatment, which renders patients susceptible to opportunistic infections and/or cancer relapse. Thus, given the additional immunosuppressive pathways involved in immune evasion in cancer, strategies that induce a faster reconstitution of key immune effector cells are needed. Natural killer (NK) cells mediate potent anti-tumor effector functions and are the first immune cells to repopulate after HSCT. TGF-β is a potent immunosuppressive cytokine that can impede both the development and function of immune cells. Here, we evaluated the use of an immunotherapeutic regimen that combines low dose of IL-2, an NK cell stimulatory signal, with TGF-β neutralization, in order to accelerate NK cell reconstitution following congenic HSCT in mice by providing stimulatory signals yet also abrogating inhibitory ones. This therapy led to a marked expansion of NK cells and accelerated NK cell maturation. Following HSCT, mature NK cells from the treated recipients displayed an activated phenotype and enhanced anti-tumor responses both in vitro and in vivo. No overt toxicities or adverse effects were observed in the treated recipients. However, these stimulatory effects on NK cell recovery were predicated upon continuous treatment as cessation of treatment led to return to baseline levels and to no improvement of overall immune recovery when assessed at later time-points, indicating strict regulatory control of the NK cell compartment. Overall, this study still demonstrates that therapies that combine positive and negative signals can be plausible strategies to accelerate NK cell reconstitution following HSCT and augment anti-tumor efficacy.

Download Full-text

Mobilization with cyclophosphamide reduces the number of lymphocyte subpopulations in the leukapheresis product and delays their reconstitution after autologous hematopoietic stem cell transplantation in patients with multiple myeloma

Radiology and Oncology ◽

10.1515/raon-2016-0028 ◽

2016 ◽

Vol 50 (4) ◽

pp. 402-408 ◽

Cited By ~ 1

Author(s):

Matevz Skerget ◽

Barbara Skopec ◽

Darja Zontar ◽

Peter Cernelc

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Nk Cells ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

T Regulatory Cells ◽

Nk Cell ◽

Hematopoietic Stem ◽

Cell Counts

Abstract Background Autologous hematopoietic stem cell transplantation is considered the standard of care for younger patients with multiple myeloma. Several mobilization regimens are currently used, most commonly growth factors alone or in combination with chemotherapy. The aim of our study was to investigate the differences in lymphocyte subpopulation counts between three different mobilization regimens on collection day, in the leukapheresis product and on day 15 after autologous hematopoietic stem cell transplantation. Patients and methods In total 48 patients were prospectively enrolled in three different mobilization regimens; (i) filgrastim (20), (ii) pegfilgrastim (19) and (iii) cyclophosphamide + filgrastim (9). Lymphocytes, CD16+/56+ natural killer and CD4+/CD25high T regulatory cells were determined by flow cytometry. Results We found a statistically significant difference between the mobilization regimens. Cyclophosphamide reduced lymphocyte and natural killer (NK) cell counts on collection day (lymphocytes 1.08 × 109/L; NK cells 0.07 × 109/L) compared to filgrastim (lymphocytes 3.08 × 109/L; NK cells 0.52 × 109/L) and pegfilgrastim (lymphocytes 3 × 109/L; NK cells 0.42 × 109/L). As a consequence lymphocyte and NK cell counts were also lower in the leukapheresis products following cyclophosphamide mobilization regimen (lymphocytes 50.1 × 109/L; NK cells 4.18 × 109/L) compared to filgrastim (lymphocytes 112 × 109/L; NK cells 17.5 × 109/L) and pegfilgrastim (lymphocytes 112 × 109/L; NK cells 14.3 × 109/L). In all mobilization regimens T regulatory cells increased 2-fold on collection day, regarding the base line value before mobilization. There was no difference in T regulatory cell counts between the regimens. Conclusions Mobilization with cyclophophamide reduces the number of mobilized and collected lymphocytes and NK cells as compared to mobilization with growth factors only and results in their delayed reconstitution following autologous hematopoietic stem cell transplantation. We found no difference between filgrastim and pegfilgrastim mobilization.

Download Full-text

Abstract 2536: Post-transplantation NK cell is a useful predictor of graft-versus-host-disease in allogeneic hematopoietic stem cell transplantation

10.1158/1538-7445.am2014-2536 ◽

2014 ◽

Author(s):

Seo Yeon Kim ◽

Hyewon Lee ◽

Hyoeun Shim ◽

Hyeon-Seok Eom ◽

Sun-Young Kong

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Graft Versus Host Disease ◽

Nk Cell ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Graft Versus Host

Download Full-text

Dynamic Changes of Inhibitory Killer-Immunoglobulin-Like Receptors on NK Cells after Allogeneic Hematopoietic Stem Cell Transplantation: An Initial Study

Journal of Clinical Medicine ◽

10.3390/jcm9113502 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3502

Author(s):

Tereza Dekojová ◽

Lucie Houdová ◽

Jiří Fatka ◽

Pavel Pitule ◽

Pavel Ostašov ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Nk Cells ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Nk Cell ◽

Ex Vivo ◽

Post Transplantation ◽

Hematopoietic Stem

Killer-immunoglobulin-like receptors (KIRs) are critical natural killer (NK) cell regulators. The expression of KIRs is a dynamic process influenced by many factors. Their ligands—HLA(Human Leukocyte Antigen) class I molecules—are expressed on all nucleated cells that keep NK cells under control. In hematopoietic stem cell transplantation (HSCT), NK cells play an essential role in relapse protection. In the presented pilot study, we characterized the dynamic expression of inhibitory KIRS (iKIRs), which protect cells against untoward lysis, in donors and patients during the first three months after HSCT using flow cytometry. The expression of all iKIRs was highly variable and sometimes correlated with patients’ clinical presentation and therapy regiment. Cyclophosphamide (Cy) in the graft-versus-host disease (GvHD) prevention protocol downregulated KIR2DL1 to just 25% of the original donor value, and the FEAM (Fludarabine + Etoposid + Ara-C + Melphalan) conditioning protocol reduced KIR2DL3. In lymphoid neoplasms, there was a slightly increased KIR2DL3 expression compared to myeloid malignancies. Additionally, we showed that the ex vivo activation of NK cells did not alter the level of iKIRs. Our study shows the influence of pre- and post-transplantation protocols on iKIR expression on the surface of NK cells and the importance of monitoring their cell surface.

Download Full-text

Influence of a Moderate-Intensity Exercise Program on Early NK Cell Immune Recovery in Pediatric Patients After Reduced-Intensity Hematopoietic Stem Cell Transplantation

Integrative Cancer Therapies ◽

10.1177/1534735416679515 ◽

2016 ◽

Vol 16 (4) ◽

pp. 464-472 ◽

Cited By ~ 11

Author(s):

Carolina Chamorro-Viña ◽

Jaime Valentín ◽

Lucía Fernández ◽

Marta González-Vicent ◽

Margarita Pérez-Ruiz ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Nk Cell ◽

Exercise Program ◽

Moderate Intensity ◽

Moderate Intensity Exercise ◽

Hematopoietic Stem

Introduction: After allogeneic hematopoietic stem cell transplantation (HSCT), NK cell reconstitution, which is crucial for positive outcomes, is dominated by the CD56bright subset with low NK cell cytotoxicity (NKCC) activity. Moderate exercise has been described as a potent NK cell stimulus in adults with cancer. Purpose: To determine the effects of a moderate-intensity exercise program on NK cell recovery early after HSCT and the feasibility of this intervention. Methods: Six children undergoing allogeneic HSCT were randomized to an exercise program (EP) or control (CT) group. The EP group performed a 10-week training combining in-hospital and home-based EP. Results: We observed a significant increase in the posttraining/pretraining ratio of the CD56dim subset (EP = 1.27 ± 0.07; CT = 0.99 ± 0.08; P < .005) of the EP group. The ratio of NKCC was 8 times greater in the EP group. Conclusion: Data suggest that a moderate-intensity EP program performed early after HSCT is feasible and might redistribute the CD56dim/CD56brigh NK cell subset, improving NKCC. The results are still preliminary and must be interpreted with caution.

Download Full-text