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

Abstract

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.

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

“…Manual gating of SIRIUS WB samples showed that there was a significant increase in granzyme B production among responders to daratumumab. This is important to note, given that recent studies have spoken to the varied functional status of both peripheral blood and BM T cells from multiple myeloma patients (40,41). Moreover, these findings align with work conducted by Chatterjee et al, which showed that inhibition of CD38 increased NAD + -dependent activity of Sirt1 and enhanced the anti-tumor effect of CD8 + T cells (42).…”

Risk factors for infections in newly diagnosed Multiple Myeloma patients: A Danish retrospective nationwide cohort study

“…Finally, immune dysfunction in MM also involves dysregulation of T cells and the innate immune system which we were not able to evaluate in the current study. [35][36][37][38][39][40] In conclusion, in our population-based study on 2557 cases of newly diagnosed symptomatic MM, we have identified ISS score of II or II, high LDH and renal impairment as specific risk factors for the development of pneumonia and/or sepsis within 6 months from diagnosis. We could not find clinical important association between immunoparesis and risk of pneumonia or sepsis.…”

“…Furthermore, we have only included infections that occurred during the first 6 months from MM diagnosis; however, it is reasonable to assume that the degree of immunoparesis changes over time and that the risk factors for infections might be different later in the disease stage. Finally, immune dysfunction in MM also involves dysregulation of T cells and the innate immune system which we were not able to evaluate in the current study …”

Immunotherapy for Multiple Myeloma

“…Exhausted T cells expressing immune checkpoint receptors are involved in disease progression in cancer models, although the role of exhausted T cells in the pathophysiology of MM remains controversial [15,80,81]. An in vivo murine myeloma model demonstrated that the expression levels of immune checkpoint receptors such as programmed cell death protein 1 (PD-1), T-cell immunoglobulin and ITIM domains (TIGIT), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin mucin-3 (Tim-3) were increased on CD8 + T cells in bone marrow in MM-relapsed mice compared with those in control mice and MM-controlled mice [82].…”