Rescue of Impaired NK Cell Activity in Hodgkin Lymphoma With Bispecific Antibodies In Vitro and in Patients

Reiners, Katrin S.; Keßler, Jörg; Sauer, Maike; Rothe, Achim; Hansen, Hinrich P.; Reusch, Uwe; Hucke, Christian; Köhl, Ulrike; Dürkop, Horst; Engert, Andreas; Strandmann, Elke Pogge von

doi:10.1038/mt.2013.14

Cited by 97 publications

(68 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Decreased NK cell cytotoxicity has been observed in many patients suffering from tumors or immunosuppressive diseases (Ziegler et al, 1981;Sirianni et al, 1990;DanielouLazareth et al, 2013;Reiners et al, 2013). Our results indicate that SMG can significantly inhibit the cytotoxicity of NK cells ( p < 0.05).…”

Section: Discussionsupporting

confidence: 67%

Effects of Simulated Microgravity on Primary Human NK Cells

Mei²,

Huyan³

et al. 2013

Astrobiology

View full text Add to dashboard Cite

The deleterious effects of microgravity on lymphocytes have been demonstrated in previous studies. However, research on the effects of microgravity on human natural killer (NK) cells remains exceedingly limited. In this study, we demonstrated that NK cell cytotoxicity was significantly decreased under simulated microgravity (SMG) conditions ( p < 0.05). Several processes, including apoptosis, receptor expression, and cytokine secretion, were investigated in human NK cells under SMG. We observed decreased cytotoxicity, concurrent with increased apoptosis and necrosis, in NK cells after exposure to SMG ( p < 0.05). Additionally, interferon (IFN)-c and perforin expression decreased significantly, and the expression of granzyme-B was only slightly reduced. Meanwhile, SMG selectively inhibited the expression of certain surface receptors on NK cells. Specifically, the expression of NKG2A and NKG2D were significantly downregulated under SMG, but the expression of NKp30 and NKp44 was not affected. We also found that interleukin (IL)-15 alone or in combination with IL-12 could counteract the inhibition of NK cell cytotoxicity under SMG. Our findings indicate that human NK cells were sensitive to SMG, as reflected by their decreased cytotoxicity. Factors such as increased early apoptosis and late apoptosis/necrosis and the decreased expression of INF-c, cytolytic proteins, and cell surface receptors may be responsible for the loss of cytotoxicity in human NK cells under SMG. A combination of IL-12 and IL-15 may be useful as a therapeutic strategy for overcoming the effects of microgravity on human NK cells during long space missions.

show abstract

Section: Discussionsupporting

confidence: 67%

Effects of Simulated Microgravity on Primary Human NK Cells

Mei²,

Huyan³

et al. 2013

Astrobiology

View full text Add to dashboard Cite

show abstract

“…This effect was transient, and total NK-cell numbers were back to baseline levels prior to the next infusion (data not shown). In parallel, the relative portion of activated NK cells, indicated by CD69 1 , increased immediately after the infusions, as reported previously by Reiners et al 25 This observation was dose independent and strongest after the first infusion. However, during the period between the infusions, activated NK cells decreased again to baseline levels prior to the next infusion.…”

Section: Response To Treatmentsupporting

confidence: 73%

“…34,35 Poppema et al have demonstrated that specific cytotoxic T-or NK-cell populations are absent in the environment of H/RS cells. 36 Reiners et al 25 investigated functional NK-cell defects and found that in peripheral blood of HL patients, NKcell function is impaired. This impairment correlated with the downregulation of the NK-cell receptors NKp30 and, in particular, NKG2D.…”

Section: Discussionmentioning

confidence: 99%

A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma

Rothe

Sasse²,

Topp

et al. 2015

Blood

Self Cite

278

216

View full text Add to dashboard Cite

(50%), with an overall disease control rate of 61.5%. AFM13 was also active in brentuximab vedotin-refractory patients. In 13 patients who received doses of ‡1.5 mg/kg AFM13, the overall response rate was 23% and the disease control rate was 77%. AFM13 treatment resulted in a significant NK-cell activation and a decrease of soluble CD30 in peripheral blood. In conclusion, AFM13 represents a welltolerated, safe, and active targeted immunotherapy of Hodgkin lymphoma. A phase 2 study is currently planned to optimize the dosing schedule in order to further improve the therapeutic efficacy. This phase 1 study was registered at www.clinicaltrials.gov as #NCT01221571. (Blood. 2015;125(26):4024-4031)

show abstract

“…However, this might be different in other tumor entities (eg, acute myeloid leukemia 16 or Hodgkin lymphoma). 45 The only variation reported so far for NK cells from CLL patients compared with NK cells from healthy donors is a slight but significant down-regulation of NKp30. 15 A decreased expression of NCRs on NK cells correlating to poor prognostic factors was also reported.…”

Section: Discussionmentioning

confidence: 99%

Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity

Reiners¹,

Topolar²,

Henke³

et al. 2013

Blood

Self Cite

190

171

View full text Add to dashboard Cite

Key Points• Exosomal NKp30-ligand BAG6 is crucial for detection of tumor cells by NK cells in vitro and in vivo.• Soluble plasma factors including BAG6 suppress NK cell cytotoxicity and promote evasion of CLL cells from NK cell anti-tumor activity.Natural killer (NK) cells are a major component of the anti-tumor immune response. NK cell dysfunctions have been reported in various hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here we investigated the role of tumor cellreleased soluble and exosomal ligands for NK cell receptors that modulate NK cell activity. Soluble CLL plasma factors suppressed NK cell cytotoxicity and downregulated the surface receptors CD16 and CD56 on NK cells of healthy donors. The inhibition of NK cell cytotoxicity was attributed to the soluble ligand BAG6/BAT3 that engages the activating receptor NKp30 expressed on NK cells. Soluble BAG6 was detectable in the plasma of CLL patients, with the highest levels at the advanced disease stages. In contrast, NK cells were activated when BAG6 was presented on the surface of exosomes. The latter form was induced in non-CLL cells by cellular stress via an nSmase2-dependent pathway. Such cells were eliminated by lymphocytes in a xenograft tumor model in vivo. Here, exosomal BAG6 was essential for tumor cell killing because BAG6-deficient cells evaded immune detection. Taken together, the findings show that the dysregulated balance of exosomal vs soluble BAG6 expression may cause immune evasion of CLL cells. (Blood. 2013;121(18):3658-3665) IntroductionChronic lymphocytic leukemia (CLL) patients suffer from severe immune defects resulting in increased susceptibility to infections and failure to generate an anti-tumor immune response. 1 Natural killer (NK) cells, lymphocytes of the innate immune system, are considered to be a major component of the immunosurveillance in leukemia. [2][3][4] However, little is known about the functionality of NK cells and their role in tumor immune escape in CLL.NK cells are tightly regulated by inhibitory or activating "missing self" and "induced self" signals sensed via cell surface receptors. 5 The best examined activating receptors are the Fc receptor CD16, NKG2D, and the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46. Known ligands for NKG2D are the major histocompatibility complex (MHC) class I-related molecules MICA/B and the UL16-binding proteins (ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, and ULBP6) that are induced upon cellular stress on target cells. 6,7 Only a few ligands for the NCRs have been identified to date. [8][9][10][11][12][13][14] Surprisingly, among novel ligands for NKp30 (BAG6 [BAT3], 10 B7-H6 11 ), NKp44 (proliferating cell nuclear antigen 12 ) and NKp46 (vimentin 13,14 ), only B7-H6 is a surface membrane ligand. BAG6, proliferating cell nuclear antigen, and vimentin are proteins without any classical transmembrane domain and are known to exert divergent intracellular functions, including protein sorting and transport, proliferation, and apoptosis. It is still ...

show abstract

Rescue of Impaired NK Cell Activity in Hodgkin Lymphoma With Bispecific Antibodies In Vitro and in Patients

Cited by 97 publications

References 49 publications

Effects of Simulated Microgravity on Primary Human NK Cells

Effects of Simulated Microgravity on Primary Human NK Cells

A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma

Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity

Contact Info

Product

Resources

About