Myeloma skews regulatory T and pro-inflammatory T helper 17 cell balance in favor of a suppressive state

Favaloro, James; Brown, Ross; Aklilu, Esther; Shi, Yang; Suen, Hayley; Hart, Derek N.J.; Fromm, Phillip D.; Gibson, John; Khoo, Liane; Ho, P. Joy; Joshua, Douglas

doi:10.3109/10428194.2013.825905

Cited by 64 publications

(47 citation statements)

References 41 publications

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“…Instead, a mechanism of isotype-specific suppression dependent on increased numbers of T cells bearing surface receptors of the respective monoclonal isotype might be more relevant, as observed in mouse models with plasmacytomas (22,23). More recently, several publications have shown that functional regulatory T cells (T-regs) were in-creased in the peripheral blood of MGUS and MM patients, and it is proposed that this could be a consequence of the malignant transformation of the clone (24,25). If indeed clone expansion stimulates the production of isotype-specific T cells with the consequent suppression of the isotypematched B-cells, severe IMI could be a more specific and precocious marker of disease progression than classical IP.…”

Section: Discussionmentioning

confidence: 99%

Severe Isotype-Matched Immunosuppression (IMI) as a Potential Risk Factor for Progression of MGUS Patients

Jiménez

Pais

Barbosa

et al. 2018

The Journal of Applied Laboratory Medicine

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Background: Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma in virtually every case. However, only a small percentage will progress and at very different rates. In addition, recent data have suggested that MGUS is associated with other comorbidities including infections, suggesting impaired immune function in some MGUS patients. Therefore, we aimed at assessing the value of isotype-matched immunosuppression (IMI; e.g., suppression of an IgAκ in an IgAλ patient), a type of immunosuppression more specific than classical immunoparesis (IP; e.g., IgG and/or IgM suppression in an IgA patient), as a prognostic marker for MGUS progression. Methods: The Hevylite assay was used to assess IMI and immunoglobulin ratios in 307 serum samples from a cohort of 248 MGUS patients. Follow-up clinical records were available for 154 individuals. Results: A greater incidence of IMI (51%) over classical IP (37%) was observed, although both show a progressive increase with higher risk groups. Survival analysis of 154 patients showed that severe IMI (>50% suppression) differentiates 2 groups with significantly different time to progression (P = 0.024) while severe IP does not (P = 0.48). Also, a combination of severe IMI and involved monoclonal immunoglobulin >1.5g/dL by Hevylite (both variables found to be independent prognostic markers in multivariate analysis) identified a group of patients with a median time to progression 6-fold shorter than the remaining group (P < 0.0001). Conclusions: These findings indicate a possible role for IMI in the malignant transformation of MGUS patients and a potential utility as a new risk factor. IMPACT STATEMENT Patients diagnosed with MGUS are at a greater risk of developing multiple myeloma or a related disease. Importantly, the conversion rate is highly heterogeneous, and hematologists rely on biomarkers to estimate the risk of progression and to decide on the clinical approach. We describe the role of a new type of immunosuppression as an independent indicator of early progression, contributing to a better characterization of the condition. This immunosuppression is characterized by decreased levels of the immunoglobulins of the same type of the tumor B-cells but of the alternative light chain, and is easily measured by a simple serum test called Hevylite ® .

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Section: Discussionmentioning

confidence: 99%

Severe Isotype-Matched Immunosuppression (IMI) as a Potential Risk Factor for Progression of MGUS Patients

Jiménez

Pais

Barbosa

et al. 2018

The Journal of Applied Laboratory Medicine

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“…T regulatory cells (Tregs) are often studied in relation to Th17 cells, as their differentiation is mutually controlled, and the Treg/Th17 balance is considered to be a marker of immunoregulatory function. 10 A skew towards an increase of the Treg/Th17 cell ratio in MM has been associated with an immunosuppressive state 26,27 and, accordingly, long-term survival in MM has been correlated with a favorable Treg/Th17 balance. 26,28 …”

Section: Th17 Cells In MMmentioning

confidence: 99%

Non-redundant roles for Th17 and Th22 cells in multiple myeloma clinical correlates

2016

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“…The composition of lymphocytes present in the MM microenvironment substantially differs from that in a healthy subject. 82,83 Under the priming of elevated concentration of IL-6 and TGF-b, T H17 cells are abundant in the BM of MM patients. 84,85 These are a distinct subset of CD4 1 T helper lymphocytes characterized by a peculiar pattern of cytokine production: IL-17, IL-17F, In the context of the BM cytokine milieu of MM patients, T H17 cells suppress cancer immune surveillance by secreting IL-17 and IL-10.…”

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confidence: 99%

Pathogenesis beyond the cancer clone(s) in multiple myeloma

Bianchi

Munshi

2015

Blood

242

224

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Over the past 4 decades, basic research has provided crucial information regarding the cellular and molecular biology of cancer. In particular, the relevance of cancer microenvironment (including both cellular and noncellular elements) and the concept of clonal evolution and heterogeneity have emerged as important in cancer pathogenesis, immunologic escape, and resistance to therapy. Multiple myeloma (MM), a cancer of terminally differentiated plasma cells, is emblematic of the impact of cancer microenvironment and the role of clonal evolution. Although genetic and epigenetic aberrations occur in MM and evolve over time under the pressure of exogenous stimuli, they are also largely present in premalignant plasma cell dyscrasia such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), suggesting that genetic mutations alone are necessary, but not sufficient, for myeloma transformation. The role of bone marrow microenvironment in mediating survival, proliferation, and resistance to therapy in myeloma is well established; and although an appealing speculation, its role in fostering the evolution of MGUS or SMM into MM is yet to be proven. In this review, we discuss MM pathogenesis with a particular emphasis on the role of bone marrow microenvironment. (Blood. 2015;125(20):3049-3058) Characteristics of the myeloma cancer clone Ontogenesis of myelomaMultiple myeloma (MM) represents the far end of the spectrum of B cell-derived neoplasms. It is the neoplastic counterpart of terminally differentiated, immunoglobulin-producing, long-lived plasma cells (PCs). Long-lived PCs are a subset of PCs characterized by long-term (months to years) survival within the bone marrow (BM) and thought to be key for immunologic memory.1,2 Based on the sequencing of the immunoglobulin heavy chain (IgH) variable region of MM cells (MMCs), the first oncogenic events in MM appear to occur in the germinal center, likely during the processes of isotype class switching and somatic hypermutation, which are, by nature, mutation prone. 3 The observation that patients with premalignant PC dyscrasia monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM) also carry these initial mutations suggests that they are necessary, but not sufficient, in MM pathogenesis. Late oncogenic events are thought to occur in the BM, after the founder cancer clone is completely differentiated into a long-lived PC (Figure 1). 4 There is ongoing debate regarding the identity of the MM stem cells. Different groups have shown that both CD138 1 and CD192 cells are capable of tumorigenesis in mouse models.However, CD138 1 tends to lose self-renewing potential after a few cycles of serial transplantation, whereas the putative B-cell stem clone was never proved to be clonally related to its putative CD138 1 progeny.Overall, modification in the cytokine composition of the media used to maintain CD138 1 ex vivo successfully overcame the first issue, suggesting that the MM stem cell may be CD1381 . 5Ev...

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Myeloma skews regulatory T and pro-inflammatory T helper 17 cell balance in favor of a suppressive state

Cited by 64 publications

References 41 publications

Severe Isotype-Matched Immunosuppression (IMI) as a Potential Risk Factor for Progression of MGUS Patients

Severe Isotype-Matched Immunosuppression (IMI) as a Potential Risk Factor for Progression of MGUS Patients

Non-redundant roles for Th17 and Th22 cells in multiple myeloma clinical correlates

Pathogenesis beyond the cancer clone(s) in multiple myeloma

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