Early alterations in stem-like/marrow-resident T cells and innate and myeloid cells in preneoplastic gammopathy

Bailur, Jithendra Kini; McCachren, Samuel S.; Doxie, Deon B.; Shrestha, Mahesh; Pendleton, Katherine E.; Nooka, Ajay K.; Neparidze, Natalia; Parker, Terri L.; Bar, Noffar; Kaufman, Jonathan L.; Hofmeister, Craig C; Boise, Lawrence H.; Lonial, Sagar; Kemp, Melissa L.; Dhodapkar, Kavita M.; Dhodapkar, Madhav V.

doi:10.1172/jci.insight.127807

Cited by 134 publications

(158 citation statements)

References 35 publications

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“…Despite in monocytes the CD64 overexpression is driven by both IL10 and IFN-γ and we have found the overexpression of ILR10B and its downstream effectors, we have not tested IL10 in vitro to recapitulate the MM-HDN phenotype since it is known that normal neutrophils do not upregulate CD64 via IL10, but only via IFN-γ 13,40,41,[69][70][71] . There is an emerging interest in identifying the molecular machinery involved in the IFN response in the MM microenvironment, since several cellular types show an IFNAR1 related signature in response to type 1 interferon secretion by myeloma cells 72 , while type 3 interferon is reduced 73 due to anergic NK and T-cells 61 also in the asymptomatic MGUS phase 74 . Further effort in our lab is currently focused to identify the source of extracellular IFN-γ in the paracrine loop sustaining MM expansion, and we have evidence of out-of-lineage, low-rate synthesis of IFN-γ in MM-HDNs 38 .…”

Section: Discussionmentioning

confidence: 99%

High-density neutrophils in MGUS and multiple myeloma are dysfunctional and immune-suppressive due to increased STAT3 downstream signaling

Romano

Parrinello

Simeon

et al. 2020

Sci Rep

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To understand neutrophil impairment in the progression from MGUS through active MM, we investigated the function of mature, high-density neutrophils (HDNs), isolated from peripheral blood. In 7 MM, 3 MGUS and 3 healthy subjects by gene expression profile, we identified a total of 551 upregulated and 343 downregulated genes in MM-HDN, involved in chemokine signaling pathway and FC-gamma receptor mediated phagocytosis conveying in the activation of STAT proteins. In a series of 60 newly diagnosed MM and 30 MGUS patients, by flow-cytometry we found that HDN from MM, and to a lesser extend MGUS, had an up-regulation of the inducible FcγRI (also known as CD64) and a down-regulation of the constitutive FcγRIIIa (also known as CD16) together with a reduced phagocytic activity and oxidative burst, associated to increased immune-suppression that could be reverted by arginase inhibitors in co-culture with lymphocytes. In 43 consecutive newly-diagnosed MM patients, who received first-line treatment based on bortezomib, thalidomide and dexamethasone, high CD64 could identify at diagnosis patients with inferior median overall survival (39.5 versus 86.7 months, p = 0.04). Thus, HDNs are significantly different among healthy, MGUS and MM subjects. In both MGUS and MM neutrophils may play a role in supporting both the increased susceptibility to infection and the immunological dysfunction that leads to tumor progression.

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Section: Discussionmentioning

confidence: 99%

High-density neutrophils in MGUS and multiple myeloma are dysfunctional and immune-suppressive due to increased STAT3 downstream signaling

Romano

Parrinello

Simeon

et al. 2020

Sci Rep

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“…However, even in patients with MGUS, increased levels of immunosuppressive regulatory T cells (Treg; ref. 9) and T-cell exhaustion (10) have been reported. An immune profiling study found that T cells from patients with SMM had an aberrant phenotypic profile, including reduced expression of activation markers, compared with those from age-matched healthy controls (5).…”

Section: Evolution Of T-cell Immunity In Multiple Myeloma Disease Promentioning

confidence: 99%

“…An immune profiling study found that T cells from patients with SMM had an aberrant phenotypic profile, including reduced expression of activation markers, compared with those from age-matched healthy controls (5). Early changes in the T-cell population, including the presence of antigen-specific immunity and an enrichment of bone marrow (BM) stem-like/resident memory (TRM) T cells may prevent attrition of protective immunity and subsequent disease progression (10)(11)(12).…”

Section: Evolution Of T-cell Immunity In Multiple Myeloma Disease Promentioning

confidence: 99%

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How to Train Your T Cells: Overcoming Immune Dysfunction in Multiple Myeloma

Cohen

Raje

Fowler

et al. 2020

Clinical Cancer Research

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The progression of multiple myeloma, a hematologic malignancy characterized by unregulated plasma cell growth, is associated with increasing innate and adaptive immune system dysfunction, notably in the T-cell repertoire. Although treatment advances in multiple myeloma have led to deeper and more durable clinical responses, the disease remains incurable for most patients. Therapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and activating the host immune system have recently shown promise in multiple myeloma, particularly in the relapsed and/or refractory disease setting. As the efficacy of T-cell-dependent immuno-oncology therapy is likely affected by the health of the endogenous T-cell repertoire, these therapies may also provide benefit in alternate treatment settings (e.g., precursor disease; after stem cell transplantation). This review describes T-cell-associated changes during the evolution of multiple myelo-ma and provides an overview of T-cell-dependent immunooncology approaches under investigation. Vaccine and checkpoint inhibitor interventions are being explored across the multiple myeloma disease continuum; treatment modalities that redirect patient T cells to elicit an anti-multiple myeloma response, namely, chimeric antigen receptor (CAR) T cells and bispecific antibodies [including BiTE (bispecific T-cell engager) molecules], have been primarily evaluated to date in the relapsed and/or refractory disease setting. CAR T cells and bispecific antibodies/antibody constructs directed against B-cell maturation antigen have generated excitement, with clinical data demonstrating deep responses. An increased understanding of the complex interplay between the immune system and multiple myeloma throughout the disease course will aid in maximizing the potential for T-cell-dependent immuno-oncology strategies in multiple myeloma.

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“…Structural defects in gut integrity cause by HIV further impacts the microbiota distribution (36), which given its ability in cancer models to modulate toxicity (37) and therapy efficacy (38,39), may represent an attractive therapeutic avenue as proposed by Herrera et al. In some respects, as describe by Dhodapkar and Dhodapkar, ART-suppressed HIV mirrors preclinical malignancy, a prolonged state characterized by earlyonset of T-cell exhaustion coupled with the depletion of stem cell memory (40). However, unlike antigen-rich tumor models, curative HIV therapies require that latent virus be reactivated to render infected cells immunogenic and cleared by potent anti-HIV CTLs ("kick and kill") (10, 41).…”

Section: Who Watches the Watchmen?mentioning

confidence: 99%

Editorial: HIV and Cancer Immunotherapy: Similar Challenges and Converging Approaches

et al. 2020

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Early alterations in stem-like/marrow-resident T cells and innate and myeloid cells in preneoplastic gammopathy

Cited by 134 publications

References 35 publications

High-density neutrophils in MGUS and multiple myeloma are dysfunctional and immune-suppressive due to increased STAT3 downstream signaling

High-density neutrophils in MGUS and multiple myeloma are dysfunctional and immune-suppressive due to increased STAT3 downstream signaling

How to Train Your T Cells: Overcoming Immune Dysfunction in Multiple Myeloma

Editorial: HIV and Cancer Immunotherapy: Similar Challenges and Converging Approaches

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