Identification of Anti-tumor Cells Carrying Natural Killer (NK) Cell Antigens in Patients With Hematological Cancers

Krzywińska, Ewelina; Allende-Vega, Nerea; Cornillon, Amélie; Vo, Dang-Nghiem; Cayrefourcq, Laure; Panabieres, C.; Vilches, Carlos; Déchanet‐Merville, Julie; Hicheri, Yosr; Rossi, Jean‐François; Cartron, Guillaume; Villalba, Martín

doi:10.1016/j.ebiom.2015.08.021

Cited by 24 publications

(79 citation statements)

References 67 publications

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“…It is possible that activation-induced isoform switching occurs in vivo at sites of viral infection or malignancy, but only those cells that revert back to a CD45RA + CD45ROphenotype can efficiently re-enter the peripheral blood. Although CD45RO expression is virtually absent on peripheral blood NK cells isolated from healthy individuals, distinct subsets of CD45RO + cells have been identified in the blood and bone marrow of individuals with various types of hematologic malignancies (60).…”

Section: Resultsmentioning

confidence: 99%

Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming

Merino

Zhang

Dougherty

et al. 2019

Journal of Clinical Investigation

136

111

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Conflict of interest:FC consults for Fate Therapeutics and has received research funds from this relationship. JSM serves on the Scientific Advisory Board (SAB) and consults for GT BioPharma and Fate Therapeutics. He has received research funds from these relationships. JSM also serves on the SAB for CytoSen and Onkimmune. BRB declares a financial conflict with Tmunity and Kadmon Corporation. He also serves on the SAB for GT Biopharma, Magenta Therapeutics, and Five Prime Therapeutics. He consults for Regeneron and Equillium Inc. None of these companies had a role in funding this research. All conflicts are managed according to institutional policies. Figure 1. Chronic stimulation through NKG2C expands adaptive NK cells. CD3/CD19-depleted PBMCs from HCMV-seropositive donors were cultured for 7 days with 10 ng/ml IL-15 and PBS, IgG2b isotype Ab, anti-NKG2A/C Ab, or anti-NKG2C Ab. (A) Representative FACS plots and summary data showing the percentages of NK cell subsets defined by expression of CD57 and NKG2C before and after a 7-day culture (n = 7). Results are from 3 independent experiments. (B) NK cells were labeled with CellTrace dye prior to culturing. Shown are FACS plots of representative donor cells stratified by CD57 and NKG2C expression and summary data (n = 6). Results are from 3 independent experiments. *P ≤ 0.05 by paired t test. P values for multiple group comparisons (A, each group vs. PBS; B, each group vs. IgG2b isotype Ab) were adjusted using the Hommel method.Study approval. The present studies involving the use of human peripheral blood products were reviewed and approved by the IRB of the University of Minnesota under protocol 9709M00134. All blood donors provided informed consent prior to donation according to Memorial Blood Bank policies. All blood samples were deidentified prior to arrival in the laboratory.

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Section: Resultsmentioning

confidence: 99%

Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming

Merino

Zhang

Dougherty

et al. 2019

Journal of Clinical Investigation

136

111

View full text Add to dashboard Cite

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“…While we observed trends for increased expression of CD27 in NK cells that persisted across WB and BM samples, and while there are conflicting hypotheses around the functional role of NK cells with this phenotype (32)(33)(34)(35), the observed trends toward increased signal intensity of CD137 combined with increased levels of activation markers CD69 and CD25 may suggest any compromised cytolytic activity could be offset to allow for daratumumab-mediated antibody-dependent cellular cytotoxicity (32). Furthermore, Krzywinska et al showed that in hematologic malignancies, NK cells with an immature profile are still able to show cytotoxic activity (36,37), and Wang et al showed that post-daratumumab NK cells are more effective at eradicating myeloma cells (38). Recently, Feng et al have demonstrated that isatuximab, another CD38-targeted monoclonal antibody, promotes NK-cell activity through interferon γ induction, as evidenced by CD107a upregulation.…”

Section: Discussionmentioning

confidence: 99%

High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action

et al. 2018

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Daratumumab is a CD38‐targeted human monoclonal antibody with direct anti‐myeloma cell mechanisms of action. Flow cytometry in relapsed and/or refractory multiple myeloma (RRMM) patients treated with daratumumab revealed cytotoxic T‐cell expansion and reduction of immune‐suppressive populations, suggesting immune modulation as an additional mechanism of action. Here, we performed an in‐depth analysis of the effects of daratumumab on immune‐cell subpopulations using high‐dimensional mass cytometry. Whole‐blood and bone‐marrow baseline and on‐treatment samples from RRMM patients who participated in daratumumab monotherapy studies (SIRIUS and GEN501) were evaluated with high‐throughput immunophenotyping. In daratumumab‐treated patients, the intensity of CD38 marker expression decreased on many immune cells in SIRIUS whole‐blood samples. Natural killer (NK) cells were depleted with daratumumab, with remaining NK cells showing increased CD69 and CD127, decreased CD45RA, and trends for increased CD25, CD27, and CD137 and decreased granzyme B. Immune‐suppressive population depletion paralleled previous findings, and a newly observed reduction in CD38 + basophils was seen in patients who received monotherapy. After 2 months of daratumumab, the T‐cell population in whole‐blood samples from responders shifted to a CD8 prevalence with higher granzyme B positivity ( P = 0.017), suggesting increased killing capacity and supporting monotherapy‐induced CD8 + T‐cell activation. High‐throughput cytometry immune profiling confirms and builds upon previous flow cytometry data, including comparable CD38 marker intensity on plasma cells, NK cells, monocytes, and B/T cells. Interestingly, a shift toward cytolytic granzyme B + T cells was also observed and supports adaptive responses in patients that may contribute to depth of response. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

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“…They constitute a heterogeneous cell population with distinct phenotypic and functional characteristics, including, but not limited to, their ability to mediate cytolytic activity (27, 28). NK cell activity is regulated by the equilibrium between signals transduced by inhibitory and activating receptors, which dictates target cell elimination and pro-inflammatory cytokine production (29, 30).…”

Section: Introductionmentioning

confidence: 99%

Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells

et al. 2016

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Mutational status of TP53 together with expression of wild-type (wt) IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments.

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Identification of Anti-tumor Cells Carrying Natural Killer (NK) Cell Antigens in Patients With Hematological Cancers

Cited by 24 publications

References 67 publications

Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming

Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming

High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action

Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells

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