Differential expression of natural killer cell activating receptors in blood versus bone marrow in patients with monoclonal gammopathy

Costello, Régis T.; Boehrer, A.; Sanchez, Carole; Mercier, Delphine Le; Baier, Céline; Treut, Thérèse Le; Sébahoun, G

doi:10.1111/imm.12082

Cited by 60 publications

(44 citation statements)

References 9 publications

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“…CD160 competes with BTLA for binding to herpes virus entry mediator (HVEM) and has been shown to negatively regulate TCR-mediated signaling [26]. Crosslinking of 2B4 on T cells decreases proliferation, and 2B4 expression is upregulated on exhausted T cells [27, 28]. In our analyses both, CD160 and 2B4, were significantly upregulated on bone marrow T cells of myeloma patients suggesting that the extent of local immune suppression might be even higher than estimated from the previous investigations.…”

Section: Resultsmentioning

confidence: 99%

T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

Zelle‐Rieser¹,

Thangavadivel²,

Biedermann³

et al. 2016

J Hematol Oncol

233

214

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BackgroundMultiple myeloma is an incurable plasma cell malignancy that is mostly restricted to the bone marrow. Cancer-induced dysfunction of cytotoxic T cells at the tumor site may be responsible for immune evasion and therapeutical failure of immunotherapies. Therefore, enhanced knowledge about the actual status of T cells in myeloma bone marrow is urgently needed. Here, we assessed the expression of inhibitory molecules PD-1, CTLA-4, 2B4, CD160, senescence marker CD57, and CD28 on T cells of naive and treated myeloma patients in the bone marrow and peripheral blood and collected data on T cell subset distribution in both compartments. In addition, T cell function concerning proliferation and expression of T-bet, IL-2, IFNγ, and CD107a was investigated after in vitro stimulation by CD3/CD28. Finally, data was compared to healthy, age-matched donor T cells from both compartments.MethodsMulticolor flow cytometry was utilized for the analyses of surface molecules, intracellular staining of cytokines was also performed by flow cytometry, and proliferation was assessed by 3H-thymidine incorporation. Statistical analyses were performed utilizing unpaired T test and Mann-Whitney U test.ResultsWe observed enhanced T cell exhaustion and senescence especially at the tumor site. CD8+ T cells expressed several molecules associated with T cell exhaustion (PD-1, CTLA-4, 2B4, CD160) and T cell senescence (CD57, lack of CD28). This phenotype was associated with lower proliferative capacity and impaired function. Despite a high expression of the transcription factor T-bet, CD8+ T cells from the tumor site failed to produce IFNγ after CD3/CD28 in vitro restimulation and displayed a reduced ability to degranulate in response to T cell stimuli. Notably, the percentage of senescent CD57+CD28− CD8+ T cells was significantly lower in treated myeloma patients when compared to untreated patients.ConclusionsT cells from the bone marrow of myeloma patients were more severely impaired than peripheral T cells. While our data suggest that terminally differentiated cells are preferentially deleted by therapy, immune-checkpoint molecules were still present on T cells supporting the potential of checkpoint inhibitors to reactivate T cells in myeloma patients in combination therapies. However, additional avenues to restore anti-myeloma T cell responses are urgently needed.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0345-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

Zelle‐Rieser¹,

Thangavadivel²,

Biedermann³

et al. 2016

J Hematol Oncol

233

214

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“…Extensive studies in the BM and PB samples from patients with MGUS and symptomatic MM have shown that T lymphocytes and NK cells become quantitatively and functionally altered in the latter stage of the disease, [31][32][33][34][35][36][37][38][39][40][41][42] thereby suggesting a relation between an impaired immune system and the transformation of MM. Conversely, we 41 and others 43 have recently shown that patients in "operational cure" (ie, .10 years progression-free survival after therapy) have unique immune signatures characterized by increased numbers of effector cytotoxic CD8 1 T lymphocytes, NK cells, B lymphocytes, and normal PCs.…”

Section: Discussionmentioning

confidence: 99%

Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis

Paiva

Mateos

Sánchez‐Abarca

et al. 2016

Blood

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“…Unfortunately, autologous NK cells from patients with MM appear to be dysfunctional. These NK cells can have an unfavourable balance between activating and inhibitory receptors (Fauriat et al, 2006;Costello et al, 2013) and can be inhibited by the products of plasma cells (Gherman et al, 1987) and the hypoxic bone marrow microenvironment itself (Sarkar et al, 2013). Furthermore possible protection by class I expression (Carbone et al, 2005;Gao et al, 2014) in some patients suggests that any successful activity against MM requires highly active NK cells, ideally from an allogeneic source.…”

mentioning

confidence: 99%

Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma

et al. 2017

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Summary Multiple myeloma (MM) is a disease with known immune dysregulation. Natural killer (NK) cells have shown preclinical activity in MM. We conducted a first-in-human study of umbilical cord blood-derived (CB) NK cells for MM patients undergoing high dose chemotherapy and autologous haematopoietic stem cell transplantation (auto-HCT). Patients received lenalidomide (10 mg) on days −8 to −2, melphalan 200 mg/m2 on day −7, CB-NK cells on day −5 and auto-HCT on day 0. Twelve patients were enrolled, 3 on each of four CB-NK cell dose levels: 5×106, 1×107, 5×107 and 1×108 CB-NK cells/kg. Ten patients had either high-risk chromosomal changes or a history of relapsed/progressed disease. There were no infusional toxicities and no graft-versus-host disease. One patient failed to engraft due to poor autologous graft quality and was rescued with a back-up autologous graft. Overall, 10 patients achieved at least a very good partial response as their best response, including 8 with near complete response or better. With a median follow-up of 21 months, 4 patients have progressed or relapsed, 2 of whom have died. CB-NK cells were detected in vivo in 6 patients, with an activated phenotype (NKG2D+/NKp30+). These data warrant further development of this novel cellular therapy.

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Differential expression of natural killer cell activating receptors in blood versus bone marrow in patients with monoclonal gammopathy

Cited by 60 publications

References 9 publications

T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis

Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma

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