Changes in bone marrow innate lymphoid cell subsets in monoclonal gammopathy: target for IMiD therapy

Bailur, Jithendra Kini; Mehta, Sameet; Zhang, Lin; Neparidze, Natalia; Parker, Terri L.; Bar, Noffar; Anderson, Tara; Xu, Mina L.; Dhodapkar, Kavita M.; Dhodapkar, Madhav V.

doi:10.1182/bloodadvances.2017012732

Cited by 31 publications

(33 citation statements)

References 25 publications

(24 reference statements)

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“…Therefore, alterations in innate lymphocytes appear to be an early feature in the evolution of gammopathies, which is consistent with prior studies (5,30). Recent studies suggest that innate cells may be targets for immunomodulatory drugs currently being explored for prevention of myeloma (5).…”

Section: Discussionsupporting

confidence: 87%

“…Tumor cells in MGUS carry the great majority of genomic alterations, including the mutational burden found in MM (2). Prior studies have demonstrated the capacity of T cells to mediate specific recognition of MGUS cells (3,4); recent data also show alterations in innate lymphoid cells in these lesions (5). Antitumor T cells are often enriched in the bone marrow of MM patients (6, 7); therapeutic adoptive transfer of bone marrow T cells is being explored in MM (8).…”

Section: Introductionmentioning

confidence: 99%

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

Bailur¹,

McCachren²,

Doxie³

et al. 2019

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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

Bailur¹,

McCachren²,

Doxie³

et al. 2019

JCI Insight

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129

139

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“…Previous studies demonstrated how lenalidomide binds the CRBN–CRL4 E3 ubiquitin ligase , increasing ubiquitination and decreasing protein levels of two of the Ikaros family members, Ikaros and Aiolos, with high specificity . A drug with similar properties to lenalidomide was recently used in a cohort of patients affected by multiple myeloma, showing IKZF3 and IKZF1 downregulation in circulating ILCs . We showed here that lenalidomide‐mediated suppression of Aiolos and Ikaros expression affect ILC3−ILC1/NK cell balance, inhibiting ILC1/NK cell differentiation while maintaining ILC3 function.…”

Section: Discussionmentioning

confidence: 57%

Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3−ILC1/NK cell transdifferentiation

et al. 2019

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The Ikaros family of transcription factors (TFs) are important regulators of lymphocyte function. However, their roles in human innate lymphoid cell (ILC) function remain unclear. Here, we found that Ikaros (IKZF1) is expressed by all ILC subsets, including NK cells, in blood, tonsil, and gut, while Helios (IKZF2) is preferentially expressed by ILC3 in tonsil and gut. Aiolos (IKZF3) followed the expression pattern of T-bet and Eomes, being predominantly expressed by ILC1 and NK cells. Differentiation of IFN-γ-producing ILC1 and NK cells from ILC3 by IL-1β plus IL-12-stimulation was associated with upregulation of T-bet and Aiolos. Selective degradation of Aiolos and Ikaros by lenalidomide suppressed ILC1 and NK cell differentiation and expression of ILC1 and NK cell-related transcripts (LEF1, PRF1, GRZB, CD244, NCR3, and IRF8). In line with reduced ILC1/NK cell differentiation, we observed an increase in the expression of the ILC3-related TF Helios, as well as ILC3 transcripts (TNFSF13B, IL22, NRP1, and RORC) and in the frequency of IL-22 producing ILC3 in cultures with IL-1β and IL-23. These data suggest that suppression of Aiolos and Ikaros expression inhibits ILC1 and NK cell differentiation while ILC3 function is maintained. Hence, our results open up for new possibilities in targeting Ikaros family TFs for modulation of type 1/3 immunity in inflammation and cancer.Keywords: Aiolos r Ikaros r ILC r lenalidomide r NK cells Additional supporting information may be found online in the Supporting Information section at the end of the article.

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“…ILCs are a new subset of innate immune cells known to be involved in the regulation of immunity, inflammation and tissue homeostasis ( 109 ). The study also reported that ILCs are increased in BM of MGUS patients compared to HDs and their functions are enhanced in MGUS but decline in patients with asymptomatic MM ( 108 ). These results thus provided evidence that ILCs are among the earliest cell subsets enriched in the tumor microenvironment during the evolution of monoclonal gammopathies and represent a possible target to prevent disease progression by acting on their IKZF1 expression.…”

Section: Immunologic Effects Of Imids- Releasing the Ikaros Checkpoinmentioning

confidence: 88%

“…More recently, a study from Bailur et al ( 108 ) reported that Pom also reduces IKZF1 and IKZF3 levels on innate lymphoid cells (ILCs) and enhances their function, as demonstrated by the increased IFN-γ production both in vitro and in vivo ( 108 ). ILCs are a new subset of innate immune cells known to be involved in the regulation of immunity, inflammation and tissue homeostasis ( 109 ).…”

Section: Immunologic Effects Of Imids- Releasing the Ikaros Checkpoinmentioning

confidence: 99%

Checkpoint Inhibition in Myeloma: Opportunities and Challenges

et al. 2018

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Despite major improvements in the treatment landscape, most multiple myeloma (MM) patients eventually succumb to the underlying malignancy. Immunotherapy represents an attractive strategy to achieve durable remissions due to its specificity and capacity for long term memory. Activation of immune cells is controlled by a balance of agonistic and inhibitory signals via surface and intracellular receptors. Blockade of such inhibitory immune receptors (termed as “immune checkpoints”) including PD-1/PD-L1 has led to impressive tumor regressions in several cancers. Preclinical studies suggest that these immune checkpoints may also play a role in regulating tumor immunity in MM. Indeed, myeloma was among the first tumors wherein therapeutic efficacy of blockade of PD-1 axis was demonstrated in preclinical models. Expression of PD-L1 on tumor and immune cells also correlates with the risk of malignant transformation. However, early clinical studies of single agent PD-1 blockade have not led to meaningful tumor regressions. Immune modulatory drugs (IMiDs) are now the mainstay of most MM therapies. Interestingly, the mechanism of immune activation by IMiDs also involves release of inhibitory checkpoints, such as Ikaros-mediated suppression of IL-2. Combination of PD-1 targeted agents with IMiDs led to promising clinical activity, including objective responses in some patients refractory to IMiD therapy. However, some of these studies were transiently halted in 2017 due to concern for a possible safety signal with IMiD-PD1 combination. The capacity of the immune system to control MM has been further reinforced by recent success of adoptive cell therapies, such as T cells redirected by chimeric-antigen receptors (CAR-Ts). There remains an unmet need to better understand the immunologic effects of checkpoint blockade, delineate mechanisms of resistance to these therapies and identify optimal combination of agonistic signaling, checkpoint inhibitors as well as other therapies including CAR-Ts, to realize the potential of the immune system to control and prevent MM.

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Changes in bone marrow innate lymphoid cell subsets in monoclonal gammopathy: target for IMiD therapy

Abstract: Key Points Altered number, subset composition, and function of bone marrow innate lymphoid cells are early events in monoclonal gammopathies. Pomalidomide therapy leads to reduction in Ikzf1 and Ikzf3 and enhanced human innate lymphoid cell function in vivo.

Cited by 31 publications

References 25 publications

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

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

Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3−ILC1/NK cell transdifferentiation

Checkpoint Inhibition in Myeloma: Opportunities and Challenges

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