Myeloid-Derived Suppressor Cells in Multiple Myeloma.

Abstract Abstract 2794 Poster Board II-770 Myeloid-derived suppressor cells (MDSCs) are a heterogeneous mix of myeloid cells in different maturation stages generated in the bone marrow. The role of MDSCs in cancer is to suppress T-cell responses, thereby likely regulating tumor progression. In mice, MDSCs are identified by the expression of the surface markers CD11b and Gr-1. Recently, Ly6G+ granulocytic (PMN-MDSC) and Ly6G− monocytic (MO-MDSC) subsets could be distinguished (Movahedi et al. Blood 2008, 111:4233-44). In multiple myeloma patients, the immune function is impaired and this is caused by an immunologically hostile microenvironment and cellular defects, such as decreased numbers of immune cells, and DC or T-cell dysfunction. However, the role of MDSCs in immune suppression in multiple myeloma is not yet described. In this study, we investigated the immunosuppressive activity and mechanism of MDSC subsets in the syngeneic and immunocompetent 5TMM mouse model (5T2 and 5T33 models). In first instance, CD11b+Ly6G− and CD11b+Ly6G+ lineage-committed myeloid MDSC subsets were detected in 5TMM-diseased bone marrow by flow cytometry. These subsets were purified via MACS from the bone marrow of naïve and 5TMM tumor-bearing mice, and analyzed for T-cell suppressive activity. Hereto, CD8+ TCR-transgenic OT-1 splenocytes were stimulated with ovalbumin protein in the presence of purified MDSC subsets, after which T-cell proliferation was measured via 3H-thymidine incorporation. Both MDSC subsets from 5TMM bone marrow were able to suppress antigen-specific T-cell responses at a higher level compared to purified MDSC subsets from normal bone marrow. On average, Ly6G− MDSCs were more suppressive than Ly6G+ MDSCs. The 5T2MM model has a tumor take of approximately 12 weeks. Three weeks after intravenous inoculation of the tumor cells, the suppressive effect of the myeloid subsets was already observed (while the plasmacytosis in the BM was very low and no detectable serum M spike was observed), indicating that T-cell suppression is an early event in MM development. To unravel the suppressive mechanism of the MDSC subsets, inhibitors were used in ovalbumin-stimulated cocultures. Ly6G− MDSC-mediated suppression was partially reversed by the iNOS inhibitor L-NMMA and the COX-2 inhibitor sc-791, both of which lower the NO concentration in culture. In contrast, superoxide dismutase and especially catalase enhance NO concentrations, resulting in enhanced T-cell suppression. None of these inhibitors had any impact on the Ly6G+ MDSC-mediated suppression. In conclusion, these data reveal the presence of MDSCs as a novel immune suppressive strategy employed by multiple myeloma cells in the bone marrow, already occurring early in the disease process. Disclosures: No relevant conflicts of interest to declare.

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Immature myeloid Gr-1+ CD11b+ cells from lipopolysaccharide-immunosuppressed mice acquire inhibitory activity in the bone marrow and migrate to lymph nodes to exert their suppressive function

Clinical Science ◽

10.1042/cs20150653 ◽

2016 ◽

Vol 130 (4) ◽

pp. 259-271 ◽

Cited By ~ 8

Author(s):

Veronica I. Landoni ◽

Daiana Martire-Greco ◽

Nahuel Rodriguez-Rodrigues ◽

Paula Chiarella ◽

Pablo Schierloh ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Lymph Nodes ◽

Inhibitory Activity ◽

Suppressor Cells ◽

T Cell Responses ◽

Myeloid Derived Suppressor Cells ◽

Suppressive Function ◽

Cell Responses ◽

Immunosuppressed Mice

LPS-induced immunosuppression, mimicking the state observed in patients with late sepsis, induced in bone marrow a population of myeloid-derived suppressor cells (Gr-1+ CD11b+) with the ability to inhibit T-cell responses and migrate to lymph nodes to exert their suppressive function.

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The Immunomodulatory Role of Lenalidomide on Prevnar® Responses in Patients with Relapsed Multiple Myeloma: A Comprehensive Analysis of the Immune Response

Blood ◽

10.1182/blood.v112.11.2772.2772 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2772-2772 ◽

Cited By ~ 6

Author(s):

Kimberly Ann Noonan ◽

Anna Ferguson ◽

Carol A. Huff ◽

Amy Emerling ◽

Stephanie Mgebroff ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Antibody Responses ◽

Cell Responses ◽

Immune Enhancement

Abstract Aim: Pre-clinical data suggest that lenalidomide imparts an immunomodulatory effect. This clinical trial in relapsed myeloma patients examined the ability of lenalidomide to augment both endogenous as well as vaccine-specific immune responses in vivo. Methods: Relapsed, lenalidomide naïve, patients treated with 3 or less prior regimens were eligible for the study. Prevnar®, a pneumococcal vaccine, was given either before or during administration of lenalidomide in two cohorts of patients. Cohort A received their first vaccination prior to administration of drug, and the second vaccine on cycle 2, day 15 of lenalidomide. Cohort B were first vaccinated on cycle 2, day 15 and then cycle 4, day 15. Patients were treated with 25mg of lenalidomide daily days 1–21 every 28 days for 6 cycles. Pneumococcal serotype titres as well as CRM-197 T cell responses quantified the B and T cell responses, respectively, to Prevnar vaccination and were correlated with lenalidomide administration. Systemic immune responsiveness was determined by delayed type hypersensitivity (DTH) responses to Candida and tetanus and quantification of cytokines in the peripheral blood (PBL) serum and bone marrow (BM) plasma. Results: A median two-fold increase in antibody responses to Prevnar was observed in cohort B, whereas cohort A demonstrated an 80% decrease in antibody titres. Antibody responses in the bone marrow were more pronounced than in blood and were greatest in Cohort B. 1.8% of the total T cell population proliferated to CRM-197 in Cohort B vs. 0% in Cohort A. Increases in DTH responses were seen in 50% of patients post lenalidomide. Luminex was utilized to measure cytokine levels pre and post lenalidomide. Globally, IL-6 levels were greatly reduced in both the BM (88% reduction) and PBL (77% reduction) samples. Both IFNγ and IL-17 were undetectable in the PBL samples, but were elevated and unchanged respectively in BM samples. Levels of IL-10 peaked in both cohorts after the first vaccination but were ultimately reduced with the administration of lenalidomide, and overall the levels were higher in the BM than PBL samples. MCP-1 and MIP-1β levels showed an overall decrease over the course of the trial. There was no alteration of IL2, IL-4, IL-5, TNFα, IL-7, IL-1 β, IL-12, IL-13, G-CSF or GM-CSF levels with the administration of lenalidomide. Conclusions: This is the first comprehensive examination of the immunomodulatory effect of lenalidomide on global and vaccine specific in vivo immune responses. We show that the most potent immune response was observed when both prime and boost vaccines were administered while receiving lenalidomide. Immune enhancement by lenalidomide was seen in both the blood and BM compartments. Of note, the serologic titres were greater in the BM than blood and the T cell responses (when observed) appeared greater in the BM. These data provide evidence of the important role of bone marrow niche in the maintenance of immune memory responses. The increased DTH response to both Candida and tetanus provides in vivo evidence of lenalidomide-mediated immune enhancement. Taken together, these data demonstrate that lenalidomide augments in vivo immune responses in patients with advanced/relapsed multiple myeloma. This study provides the rationale for utilizing this drug in combination with cancer vaccines to augment anti-tumor efficacy or with infectious vaccines. Figure Figure

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Pparα Ablation Suppresses T Cell Responses and Anti-Tumor Immunity By Compromising the Antigen-Presenting Properties of Tumor-Associated Macrophages

Blood ◽

10.1182/blood-2021-149071 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 438-438

Author(s):

Anthos Christofides ◽

Carol Cao ◽

Qi Wang ◽

Natalia M Tijaro-Ovalle ◽

Eirini Konstantinidou ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Suppressor Cells ◽

T Cell Responses ◽

Innate Immune ◽

Myeloid Derived Suppressor Cells ◽

Cell Responses

Abstract Peroxisome proliferator activated receptors (PPARs) are transcription factors that belong to nuclear hormone superfamily, with three distinct types identified: PPARapha (PPARα), PPARgamma (PPARγ), and PPARbeta/delta (PPARβ/δ). PPARs possess a critical role in the regulation of lipid metabolism, and thus play critical roles in the differentiation and fate of immune cells. PPARα is involved in lipid and carbohydrate metabolism and PPARα agonists, such as fibrates, have been used for the treatment of hypertriglyceridemia and cardiovascular diseases. PPARα has an anti-inflammatory role during infection, and similar to PPARγ, affects the polarization of macrophages. In acute myelogenous leukemia (AML), PPARα mutations correlate with chemoresistance, poor treatment outcomes and unfavorable prognosis. In experimental tumor models, it has been proposed that PPARα agonists might enhance anti-tumor T cell responses during PD-1 blocking immunotherapy. To dissect the mechanistic role of PPARα in tumor immunity, we used mice with global deletion of PPARα and examined tumor growth and profile of the immunological landscape, using various syngeneic tumor models. Significantly larger B16-F10 melanoma and MC-17 fibrosarcoma tumors were observed in PPARα KO mice compared with wild-type control, suggesting that PPARα deletion attenuated the immunological response against cancer. To dissect the role of PPARα in key populations of the innate and adaptive immune system involved in anti-tumor responses, we analyzed the immunological landscape of tumor, tumor draining lymph nodes (TDLN) and spleen, 14-16 days after tumor implantation. Assessment of CD4 + and CD8 + T cells, CD11b +F4/80 + tumor-associated macrophages (TAMs), CD11b +Ly6C hiLy6G - monocytic myeloid derived suppressor cells (M-MDSC), and CD11b +Ly6C loLy6G + polymorphonuclear myeloid derived suppressor cells (PMN-MDSC), by using flow cytometry, showed no quantitative differences between the two experimental groups. Functionally, MDSC from PPARα KO and WT mice showed comparable immunosuppressive properties as determined by suppression assay using splenocytes from OTI transgenic mice. However, PPARα KO TAMs demonstrated a less activated state, as determined by the lower expression levels of MHC-II that is critical for antigen presentation, and CD86 that is critical for T cell costimulation and prevention of T cell anergy and exhaustion. In agreement with these properties of TAMs, CD4 + T cells from TDLN of PPARα KO mice had diminished expression of activation markers, including PD-1, PD-L1 and ICOS, and numerically decreased central memory-like CD4 + T cells (T CM), compared to control tumor bearing mice. Furthermore, CD69, an emerging marker of T cell exhaustion, was significantly upregulated in CD4 + and CD8 + T cells from the TDLN of PPARα KO mice. To determine whether PPARα ablation altered the cell intrinsic properties of myeloid cells and/or T cells resulting in impaired anti-tumor function, we examined in vitro responses of isolated populations. In response to activation via TCR/CD3 and CD28, PPARα deficient T cells had no significant differences in expansion and cytokine production compared to control. In contrast, PPARα deficient Ly6C + monocytes isolated from the bone marrow displayed diminished responses to TLR-mediated signaling as determined by production of IL-6 and TNFα. Our in vitro and in vivo findings reveal a dominant role of PPARα in regulating the fate of innate immune cells thereby altering T cell responses and anti-tumor function. Our findings have implications for the development of new therapeutic approaches to enhance innate immune cell function for the improvement of cancer immunotherapy. Disclosures No relevant conflicts of interest to declare.

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