Abstract
PURPOSE:
The report of cereblon being the target for immunomodulatory drugs, and the subsequent degradation of Ikaros (IKZF1) and Aiolos (IKZF3) was a milestone in the understanding of their mechanism of action. While recent studies have described the role of IKZF1/3 proteins in multiple myeloma (MM) cells, few have highlighted the significance of IKZF1/3 expression in T-cells.
PATIENTS AND METHODS:
We analysed the IKZF1/3 expression levels in T-cells from 38 healthy donors (HD), 43 patients with monoclonal gammopathy of undetermined significance (MGUS), 45 patients with asymptomatic MM stage I (MMI) and 50 symptomatic patients with MM stage III (MMIII), diagnosed using Durie-Salmon staging system, by flow cytometry to examine their prognostic and predictive value. We also combined in vivo observations with in vitro assays to determine the effect of IKZF1/3 expression on the T-cell immunophenotype and anti-tumour T-cell response in 162 MMIII patients.
RESULTS:
Flow cytometry analyses revealed marked differences in the frequency of T-cells expressing IKZF1/3 proteins in patients with different plasma cell diseases, patients with MMIII exhibited significantly higher IKZF3 expressing cells than HD, MGUC and MMI patients (Figure 1.A). We found that high IKZF3, but not IKZF1, expression in T-cells correlates with superior overall survival in MMIII patients treated with immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide, Figure 1.B). Moreover, we show that higher IKZF3 expression in T-cells inhibits myeloma-specific T-cell response in vitro (Figure 1.C) and patients with high IKZF3 expression exhibit increased T-cell response to lenalidomide compared to patients with low IKZF3 expression (Figure 1.D). We also show that the immunophenotype of newly diagnosed MMIII patients with high IKZF3 expressing T-cells frequency shows features of immunodeficiency that are contrary to the changes induced by immunomodulatory drugs (Figure 1.E). Although we observed higher IKZF3 expression in T-cells from patients with MMIII compared to MMI, IKZF3 expression was unaffected by the tumour microenvironment.
CONCLUSION:
In conclusion, IKZF3 expression in T-cells is a predictive value for clinical outcome in MMIII patients treated with immunomodulatory drugs due to its profound modulation of T-cell functionality.
An accompanying immunological study to registered GMMG study ID: NCT02495922:
https://clinicaltrials.gov/ct2/show/NCT02495922
Awwad: Bristol-Myers Squibb: Other: Travel, Accommodations, Expenses. Kriegsmann: BMS: Research Funding; Celgene: Research Funding. Hillengass: BMS: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; honoraria from Amgen, BMS, Celgene: Honoraria; Takeda: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Raab: Celgene: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Munder: Consultancy: Janssen-Cilag, BMS, Takeda, Amgen, Celgene.: Consultancy; Celgene: Consultancy; Amgen: Consultancy; BMS: Consultancy; Takeda: Consultancy. Weisel: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salwender: Takeda: Honoraria; Amgen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Honoraria and travel support: Janssen Cilag, Celgene, BMS.: Honoraria, Other: Travel support. Hänel: Novartis: Honoraria; Roche: Honoraria. Fenk: Honoraria and travel grants: Celgene, Janssen, BMS; research funding: Celgene.: Honoraria. Dürig: Lead Discovery Center: Research Funding. Goldschmidt: Chugai: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hundemer: Research Support BMS, Celgene, Sanofi, Morphosys.: Research Funding.
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