CD137 Identifies a Population of Regulatory T Cells That Inhibit Anti-Tumor Immune Responses In Adoptive Immunotherapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2093-2093
Author(s):  
Matthew J Goldstein ◽  
Holbrook E Kohrt ◽  
Roch Houot ◽  
Bindu Varghese ◽  
Jack T Lin ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Adoptive Immunotherapy ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Surface Markers ◽  
Cd4 Cells ◽  
Treg Population

Abstract Abstract 2093 Background: Adoptive immunotherapy is a promising novel approach to the treatment of cancer. However, clinical translation of adoptively transferred CD4 T cells is limited by cotransfer of an inhibitory population of regulatory CD4 T cells (Tregs). We identified a method of isolating viable antitumor CD4 T cells while excluding Tregs based on two surface markers—CD44 and CD137. Methods: We have developed a model for adoptive cell therapy of lymphoma whereby anti-tumor T cells are generated in vivo through vaccination with a CpG-loaded whole cell vaccine (CpG/H11). These vaccine-induced cells can protect from lethal tumor challenge when isolated and transferred into lethally irradiated, syngeneic recipient mice. We investigated the subsets of T cells involved in the anti-tumor response through a combination of in vitro and in vivo assays. Results: Adoptive transfer of CD137negCD44hi CD4 T cells, but not other sub-populations, provided protection from B cell lymphoma. We demonstrate that the population of CD137posCD44hi CD4 T cells consists primarily of activated Tregs. In vitro, these CD137pos cells suppressed the proliferation of effector cells in a contact-dependent manner. We observed that this CD137pos Treg population persisted following adoptive transfer and maintained expression of FoxP3 as well as CD137. Moreover, the addition of CD137posCD44hi CD4 cells to CD137negCD44hi CD4 cells suppressed the antitumor immune response. In the presence of CD137posCD44hi CD4 T cells, homing of other T cell populations to tumor sites was disrupted. These results suggest that CD137 expression on CD4 T cells defines a population of activated Tregs that prevent antitumor immune responses. Conclusions: Our findings identify two surface markers that can be used to facilitate the enrichment of anti-tumor CD4 T cells while depleting an inhibitory Treg population. This approach has direct applicability to clinical trials for patients with lymphoma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Selective elimination of immunosuppressive T cells in patients with multiple myeloma

Leukemia ◽  
2021 ◽  
Author(s):  
Mohamed H. S. Awwad ◽  
Abdelrahman Mahmoud ◽  
Heiko Bruns ◽  
Hakim Echchannaoui ◽  
Katharina Kriegsmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Immune Responses ◽  
High Frequency ◽  
Surface Markers ◽  
Selective Elimination ◽  
Related Transcription Factor ◽  
Cell Membrane Protein

AbstractElimination of suppressive T cells may enable and enhance cancer immunotherapy. Here, we demonstrate that the cell membrane protein SLAMF7 was highly expressed on immunosuppressive CD8+CD28-CD57+ Tregs in multiple myeloma (MM). SLAMF7 expression associated with T cell exhaustion surface markers and exhaustion-related transcription factor signatures. T cells from patients with a high frequency of SLAMF7+CD8+ T cells exhibited decreased immunoreactivity towards the MART-1aa26–35*A27L antigen. A monoclonal anti-SLAMF7 antibody (elotuzumab) specifically depleted SLAMF7+CD8+ T cells in vitro and in vivo via macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Anti-SLAMF7 treatment of MM patients depleted suppressive T cells in peripheral blood. These data highlight SLAMF7 as a marker for suppressive CD8+ Treg and suggest that anti-SLAMF7 antibodies can be used to boost anti-tumoral immune responses in cancer patients.

scholarly journals IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells

Blood ◽  
2012 ◽  
Vol 120 (17) ◽  
pp. 3478-3487 ◽  
Author(s):  
Solenne Vigne ◽  
Gaby Palmer ◽  
Praxedis Martin ◽  
Céline Lamacchia ◽  
Deborah Strebel ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Interleukin 1 ◽  
Th1 Cell ◽  
Critical Function ◽  
Mediators Of Inflammation ◽  
Th1 Polarization

AbstractThe interleukin-1 (IL-1) superfamily of cytokines comprises a set of pivotal mediators of inflammation. Among them, the action of IL-36 cytokines in immune responses has remained elusive. In a recent study, we demonstrated a direct effect of IL-36 on immune cells. Here we show that, among T cells, the IL-36 receptor is predominantly expressed on naive CD4+ T cells and that IL-36 cytokines act directly on naive T cells by enhancing both cell proliferation and IL-2 secretion. IL-36β acts in synergy with IL-12 to promote Th1 polarization and IL-36 signaling is also involved in mediating Th1 immune responses to Bacillus Calmette-Guerin infection in vivo. Our findings point toward a critical function of IL-36 in the priming of Th1 cell responses in vitro, and in adaptive immunity in a model of mycobacterial infection in vivo.

scholarly journals Blockade of the P2Y12 signaling Pathway with Clopidogrel Restrains Treg Proliferation In Vivo during Sepsis and in Vitro

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2413-2413
Author(s):  
Harika Vemulapalli ◽  
Albayati Samara ◽  
Alexander Y Tsygankov ◽  
Elisabetta Liverani
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Cd4 T Cells ◽  
Human Platelets ◽  
Positive Staining ◽  
Treg Population ◽  
Population Sizes ◽  
Aggregation Of Platelets

Abstract Sepsis is a complex clinical syndrome resulting from a serious bloodstream infection. With hospital mortality rates of affected patients reportedly as high as 50%, improved methods for treating sepsis are urgently needed. To begin development of new pharmacologic therapies, we investigated the effect of an antiplatelet treatment on the proliferation of regulatory T cells (Tregs) in a murine model of sepsis. Tregs are a subset of T lymphocytes that downregulate the immune response and promote the resolution of inflammation. Septic patients have elevated levels of circulating Tregs, and this increased prevalence is associated with increased patient mortality. Platelets, which regulate inflammation through cell-cell interactions and through secretion of inflammatory mediators,have been shown to alter the proliferation and activation of Tregs in vitro. However, the influence of platelets on Tregs in vivohas not been fully investigated. We propose that suppression of platelet functions during sepsis may restrain Treg proliferation, leading to the restoration of immunological homeostasis. To study the influence of platelets on Treg proliferation in vivo, we blocked the P2Y12signaling pathway and measured the resulting population sizes of Tregs in septic mice. P2Y12is a Giprotein-coupled purinergic receptor present on platelet surfaces. Stimulation of P2Y12by ADP leads to platelet aggregation and potentiation of platelet secretion. To block the P2Y12signaling pathway, we used the P2Y12antagonist clopidogrel. To induce sepsis in mice, we used cecal ligation and puncture (CLP). Clopidogrelwas administered orallywith a loading dose (30 mg/kg in PBS) one day before surgery and a maintenance dose (10 mg/kg in PBS) two hours prior to surgery. The nonseptic mice in the negative control group (sham) were treated with PBS only. Twenty-four hours after surgery, we isolated cells from the spleens of the mice in each treatment group (sham, CLP, and CLP with clopidogrel) and measured Treg population sizes by incubating the cells with anti-CD4, anti-CD25,and anti-Foxp3 antibodies. Tregs were identified by their positive staining for CD4, CD25, and Foxp3. We found that Tregpopulation sizes were reduced in the septic mice treated with clopidogrel compared with those in the untreated septic mice (Figure 1A).Additionally, we used flow cytometry (forward and side light scattering) to investigatewhether P2Y12antagonism altered the aggregation of platelets and CD4+T cells in whole blood.Platelets and CD4+T cells wereidentified by their positive staining with PE-anti CD41 and FITC-anti CD4, respectively. Events that were double positive for FITC and PE were identified as aggregates and reported as a percentage of gated CD4+T cells.We found that aggregation of platelets and CD4+T cells was reduced in the septic mice treated with clopidogrel (15 ±5 %) compared with that in the untreated septic mice (38 ±6 %) (n= 3, p<0.05 treated CLP vs. untreated CLP). We investigated the effect of blocking the P2Y12signaling pathway in vitrousing co-cultures of human platelets and T cells. Human platelets and T cells were isolated from healthy donors and cultured in the presence or absence of anti-CD3/CD28 (5 μg/mLeach) antibodies for 5 days at 37°C in a humidified atmosphere containing 5% CO2. To block the P2Y12signaling pathway in vitro, we used AR-C69931MX (100 nM). We measured Treg population sizes using flow cytometry as described above. We found that Treg population sizes increased when resting T cells were exposed to platelets, AR-C, or both (Figure 1B). In contrast, we found that Treg population sizes decreased when CD3/CD28-stimulated T cells were exposed to a combination of platelets and AR-C (Figure 1B). Our data indicate that blockade of the P2Y12signaling pathway changes how platelets influence T cells in vitro, depending on whether the T cells have been activated. In conclusion, blockade of the P2Y12signaling pathway restrains Treg proliferation in vivoand in vitro. Our study indicates that targeting platelets to control Treg proliferation and activity may be a promising strategy for treating sepsis. Disclosures No relevant conflicts of interest to declare.

scholarly journals In Vivo Priming of Cd4 T Cells That Produce Interleukin (Il)-2 but Not IL-4 or Interferon (Ifn)-γ, and Can Subsequently Differentiate into IL-4–Or IFN-γ–Secreting Cells

2001 ◽  
Vol 194 (8) ◽  
pp. 1069-1080 ◽  
Author(s):  
Xiaowen Wang ◽  
Tim Mosmann
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Cell Receptor ◽  
Th2 Cells ◽  
Effector Cells ◽  
Ifn Γ

The differentiation of antigen-stimulated naive CD4 T cells into T helper (Th)1 or Th2 effector cells can be prevented in vitro by transforming growth factor (TGF)-β and anti–interferon (IFN)-γ. These cells proliferate and synthesize interleukin (IL)-2 but not IFN-γ or IL-4, and can differentiate into either Th1 or Th2 cells. We have now used two-color Elispots to reveal substantial numbers of primed cells producing IL-2 but not IL-4 or IFN-γ during the Th1- or Th2-biased immune responses induced by soluble proteins or with adjuvants. These cells were CD4+CD44high and were present during immediate and long-term immune responses of normal mice. Naive T cell receptor for antigen (TCR) transgenic (DO11.10) T cells were primed in vivo after adoptive transfer into normal hosts and FACS® cloned under conditions that did not allow further differentiation. After clonal proliferation, aliquots of each clone were cultured in Th1- or Th2-inducing conditions. Many in vivo–primed cells were uncommitted, secreting IL-2 but not IL-4 or IFN-γ at the first cloning step, but secreting either IL-4 or IFN-γ after differentiation in the appropriate conditions. These in vivo-primed, uncommitted, IL-2–producing cells may constitute an expanded pool of antigen-specific cells that provide extra flexibility for immune responses by differentiating into Th1 or Th2 phenotypes later during the same or subsequent immune responses.

Enhancing the Efficacy of T Cell Receptor (TCR) Gene Therapy by Co-Transfer of TCR and Additional CD3 Molecules Into CD4+ T Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2044-2044
Author(s):  
Emma K Nicholson ◽  
Maryam Ahmadi ◽  
Angelika Holler ◽  
Rebecca Pike ◽  
Ben Carpenter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Specific Antigen ◽  
Surface Expression ◽  
Class I ◽  
Tumour Regression

Abstract Abstract 2044 Introduction: The specificity of T cells can be redirected using retroviral T cell receptor (TCR) gene transfer. This has the potential to generate tumour specific T cells that can be adoptively transferred to target defined tumour antigens. The majority of TCR gene therapy studies have focused on the transfer of TCR genes into CD8 T cells. However the transfer of antigen specific CD8 T cells in the absence of antigen specific CD4 T cells leads to impaired anti-tumour responses and impaired memory development in vivo. Class I restricted TCR can be used to transduce CD4 T cells for use in adoptive transfer. The majority of class I restricted TCRs are CD8 dependent and thus require co-transduction of CD8 to be fully functional in CD4 T cells. CD4 T cells transduced with the class I restricted F5-TCR (specific for influenza peptide NP presented by H2-Dbclass I molecules) produce IL-2 and proliferate in vitro in response to class II negative tumour cells expressing NP peptide but these cells were not able to generate an IFN-γ response. In vivo, F5-TCR CD4 T cells could provide help for F5-TCR CD8 T cell mediated tumour eradication. These F5-TCR CD4 T cells persisted in vivo for up to 90 days post tumour regression and were able to re-expand following tumour challenge. In order to improve the function of class I restricted TCR expressing CD4 T cells, we co-transduced a vector containing all 4 chains of the CD3 complex. High surface expression of TCR has been shown to correlate with increased responsiveness to specific antigen. When additional TCR is introduced into a T cell, the introduced T cell must compete with the endogenous TCR for binding to CD3. The amount of CD3 within the cell will thus be rate limiting for the level of surface expression of the introduced TCR. Method: The retroviral vectors pMP71-F5α-2A-F5β (F5-TCR) and pMP71-CD3-ζ-2A-ε-2A-δ-2A-γ-IRES-GFP (CD3) were used for retroviral transduction. CD4 splenocytes obtained from C57BL/6 mice were activated with CD3/CD28 magnetic beads for 24 hours prior to transduction with either F5-TCR alone or F5-TCR and CD3. 5 days post transduction, transduced T cells were stimulated with C57BL/6 splenocytes loaded with NP (relevant) peptide or WT1 (irrelevant) peptide and cytokine production was measured by ELISA and intracellular cytokine staining and proliferation by [3H] thymidine incorporation. For in vivo tumour challenge, C57BL/6 recipient mice were irradiated with 5.5Gy and injected subcutaneously with 1 × 106 EL4-NP-luciferase cells (a lymphoma cell line stably transfected with NP peptide and luciferase) on day 0. On day 1, mice received 1 × 106 F5-TCR CD3 CD4 T cells or 1 × 106 F5-TCR CD4 T cells or 1 × 106 Mock Transduced T cells. Tumour area was measured by calipers and by bioluminescence imaging. For T cell trafficking experiments, the experimental set up was as above but transgenic CD4 luciferase T cells were used for adoptive transfer and EL4-NP luciferase negative cells were used for tumour challenge. Results: CD4 T cells transduced with F5-TCR and CD3 had a 5-fold higher expression of F5-TCR compared to cells transduced with F5-TCR alone. In vitro, F5-TCR CD3 CD4 T cells showed increased proliferation and increased production of IL-2 and IFN-γ in response to specific antigen compared to F5-TCR CD4 T cells. F5-TCR CD3 CD4 T cells responded to at a 2-fold lower concentration of specific peptide than F5-TCR CD4 T cells. Following adoptive transfer in murine models, F5-TCR CD3 CD4 T cells eradicated NP expressing EL4 tumours but transfer of equivalent doses of F5-TCR CD4 T cells did not lead to tumour regression. Using bioluminescence imaging, F5-TCR CD3 CD4 T cells trafficked to tumour site faster and accumulated in greater numbers than F5-TCR CD4 T cells. Following tumour challenge, there were higher numbers of F5-TCR CD3 CD4 T cells persisting in bone marrow, lymph node and peripheral blood than in mice that received F5-TCR CD4 T cells. Conclusion: Increased surface expression of class I restricted TCR in CD4 T cells leads to increased sensitivity to peptide in vitro and higher levels of proliferation and cytokine production in response to specific peptide. This translates in vivo to enhanced persistence of F5-TCR CD3 CD4 T cells and more efficient trafficking to tumour site and superior tumour protection. Therefore, the co-transduction of additional CD3 can improve the function of class I restricted TCR in CD4 T cells. Disclosures: Stauss: Cell Medica: Scientific Advisor Other.

scholarly journals In vivo induction of tolerance in murine CD4+ cell subsets.

1993 ◽  
Vol 178 (5) ◽  
pp. 1637-1644 ◽  
Author(s):  
C G Romball ◽  
W O Weigle
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Tolerance Induction ◽  
Cd4 Cells ◽  
T Helper 1 ◽  
Human Gamma Globulin ◽  
Induction Of Tolerance

The induction of tolerance in mice to preparations of deaggregated human gamma globulin (DHGG) results in in vitro antigen-specific unresponsiveness in CD4+ T cells as well as in both the T helper 1 (Th1) and Th2-like subpopulations. Whereas both CD45RB(hi) and CD45RB(lo) cells from lymph nodes of HGG/complete Freund's adjuvant-immunized mice (control) proliferated in vitro to HGG, both subpopulations from mice previously tolerized with DHGG failed to respond. Furthermore, CD4+ T cells from control, but not from DHGG-injected mice, secreted high levels of interleukin 2 (IL-2) after in vitro stimulation with HGG. Although significant levels of IL-4 in supernatants of control CD4+ cells stimulated with HGG were detected in some, but not all, experiments, significant levels of IL-4 were never detected in supernatants of HGG-stimulated tolerant CD4+ cells. The demonstration that serum IgG1 anti-HGG is preferentially produced in a few tolerant mice that exhibit a leaky tolerant state suggests that tolerance induction may be more difficult to induce in IL-4- than in IL-2-producing cells.

scholarly journals CD4+ T Cells in Lymph Nodes of UVB-Irradiated Mice Suppress Immune Responses to New Antigens Both In Vitro and In Vivo

2007 ◽  
Vol 127 (4) ◽  
pp. 915-924 ◽  
Author(s):  
Shelley Gorman ◽  
Jamie W.-Y. Tan ◽  
Stephanie T. Yerkovich ◽  
John J. Finlay-Jones ◽  
Prue H. Hart
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Cd4 T Cells

Rap1-GTP Promotes the Generation of Regulatory T Cells in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 110-110
Author(s):  
Lequn Li ◽  
Rebecca Greenwald ◽  
Esther M. Lafuente ◽  
Dimitrios Tzachanis ◽  
Alla Berezovskaya ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 Cells

Abstract Elucidating the mechanisms that regulate T cell activation and tolerance in vivo will provide insights into the maintenance of physiologic homeostasis and will facilitate development novel strategies for induction of transplantation tolerance. Transient activation of the small GTPase Rap1 is one of the physiologic consequences of TCR ligation and is mandatory for β1 and β2 integrin-mediated adhesion. In contrast, sustained increase of active Rap1 inhibits T cell activation and IL-2 transcription in vitro. In order to understand the role of Rap1 in the immune responses of the intact host we generated transgenic (Tg) mice, which express the active Rap1 mutant Rap1E63 in T cells. Rap1E63-Tg mice had no defects in thymocyte development or maturation. Rap1E63-Tg thymocytes were capable of activating Ras and Erk1/2 and, compared to wild type (WT) thymocytes, displayed enhanced LFA-1:ICAM-1-mediated adhesion and increased proliferation in response to anti-CD3. Surprisingly, although lymph node and splenic CD4+ cells from the Rap1E63-Tg mice also displayed increased LFA-1:ICAM-1-mediated adhesion, they had significantly impaired activation of Erk1/2 and dramatically reduced proliferation and IL-2 production in response to anti-CD3 and WT antigen presenting cells (APC). The defective responses of CD4+ T cells suggest that Rap1E63-Tg mice may have impaired helper function in vivo. To address this issue we immunized Rap1E63-Tg and WT mice with TNP-OVA, a T-cell dependent antigen. Total IgG, IgG1 and IgG2a were dramatically reduced, indicating that Rap1E63-Tg mice had a defect in immunoglobulin class switching, consistent with defective helper T cell-dependent B cell activation. Because these results suggest that Rap1E63-Tg CD4+ cells may have an anergic phenotype, we tested rechallenge responses. We immunized Rap1E63-Tg and WT mice with TNP-OVA in vivo and subsequently we rechallenged T cells in vitro with WT APC pulsed with OVA. Compared with WT, Rap1E63-Tg T cells had dramatically reduced proliferation, IFN- γ and IL-2 production on rechallenge, findings consistent with T cell anergy. Using suppression subtraction hybridization we determined that Rap1E63 induced mRNA expression of CD103, a marker that defines a potent subset of regulatory T cells (Treg). Strikingly, Rap1E63-Tg mice had a 5-fold increase of CD103+CD25+CD4+ Treg compared to WT mice. Rap1E63-Tg CD103+CD25+CD4+ Treg expressed the highest level of Foxp3 among all T cell subsets and had the most potent inhibitory effect on proliferation and IL-2 production when added into cultures of WT CD4+CD25− cells. Importantly, removal of the CD103+ cells significantly restored Erk1/2 activation, proliferation and IL-2 production of Rap1E63-Tg CD4+ T cells. Generation of CD103+ Treg occurs after thymic development and requires encounter of peripheral autoantigen. Consistent with this, differences in CD103+ Treg were detected only between lymph node and splenic cells and not between thymocytes from Rap1E63-Tg and WT mice. Since generation of CD103+ Treg depends on the strength of TCR signal, these results suggest that by enhancing adhesion, active Rap1 regulates the generation of Treg. Moreover, these results provide evidence that active Rap1 is a potent negative regulator of immune responses in vivo and have significant implications for the development of immune-based therapies geared towards tolerance induction.

Comparison of In Vitro and In Vivo Effects of Infliximab on Cytokine Production in Proliferating CD4+ T Cells in Patients with Rheumatoid Arthritis

2015 ◽  
Vol 1 (2) ◽  
pp. 122-128
Author(s):  
Syuichi Koarada ◽  
Yuri Sadanaga ◽  
Natsumi Nagao ◽  
Satoko Tashiro ◽  
Rie Suematsu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Cytokine Production

scholarly journals Reovirus-induced cell-mediated immunity for the treatment of multiple myeloma within the resistant bone marrow niche

2021 ◽  
Vol 9 (3) ◽  
pp. e001803
Author(s):  
Louise M E Müller ◽  
Gemma Migneco ◽  
Gina B Scott ◽  
Jenny Down ◽  
Sancha King ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Immune Responses ◽  
Stromal Cells ◽  
Tumor Burden ◽  
Effector Memory ◽  
In Vivo Model ◽  
Bm Niche

BackgroundMultiple myeloma (MM) remains an incurable disease and oncolytic viruses offer a well-tolerated addition to the therapeutic arsenal. Oncolytic reovirus has progressed to phase I clinical trials and its direct lytic potential has been extensively studied. However, to date, the role for reovirus-induced immunotherapy against MM, and the impact of the bone marrow (BM) niche, have not been reported.MethodsThis study used human peripheral blood mononuclear cells from healthy donors and in vitro co-culture of MM cells and BM stromal cells to recapitulate the resistant BM niche. Additionally, the 5TGM1-Kalw/RijHSD immunocompetent in vivo model was used to examine reovirus efficacy and characterize reovirus-induced immune responses in the BM and spleen following intravenous administration. Collectively, these in vitro and in vivo models were used to characterize the development of innate and adaptive antimyeloma immunity following reovirus treatment.ResultsUsing the 5TGM1-Kalw/RijHSD immunocompetent in vivo model we have demonstrated that reovirus reduces both MM tumor burden and myeloma-induced bone disease. Furthermore, detailed immune characterization revealed that reovirus: (i) increased natural killer (NK) cell and CD8+ T cell numbers; (ii) activated NK cells and CD8+ T cells and (iii) upregulated effector-memory CD8+ T cells. Moreover, increased effector-memory CD8+ T cells correlated with decreased tumor burden. Next, we explored the potential for reovirus-induced immunotherapy using human co-culture models to mimic the myeloma-supportive BM niche. MM cells co-cultured with BM stromal cells displayed resistance to reovirus-induced oncolysis and bystander cytokine-killing but remained susceptible to killing by reovirus-activated NK cells and MM-specific cytotoxic T lymphocytes.ConclusionThese data highlight the importance of reovirus-induced immunotherapy for targeting MM cells within the BM niche and suggest that combination with agents which boost antitumor immune responses should be a priority.

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