Systemic administration of IL‐33 induces a population of circulating KLRG1^hi type 2 innate lymphoid cells and inhibits type 1 innate immunity against multiple myeloma

Abstract

Type 2 innate lymphoid cells (ILC2s) are important producers of type 2 cytokines whose role in hematological cancers remains unclear. ILC2s are a heterogeneous population encompassing distinct subsets with different tissue localization and cytokine responsiveness. In this study, we investigated the role of bone marrow (BM) ILC2s and interleukin (IL)‐33‐stimulated ILC2s in multiple myeloma, a plasma cell malignancy that develops in the BM. We found that myeloma growth was associated with phenotypic and functional alterations of BM ILC2s, characterized by an increased expression of maturation markers and reduced cytokine response to IL‐2/IL‐33. We identified a population of KLRG1hi ILC2s that preferentially accumulated in the liver and spleen of Il2rg−/− Rag2−/− mice reconstituted with BM ILC2s. A similar population of KLRG1hi ILC2s was observed in the blood, liver and spleen of IL‐33‐treated wild‐type mice. The presence of KLRG1hi ILC2s in ILC2‐reconstituted Il2rg−/− Rag2−/− mice or in IL‐33‐treated wild‐type mice was associated with increased eosinophil numbers but had no effect on myeloma progression. Interestingly, while decreased myeloma growth was observed following treatment of Rag‐deficient mice with the type 1 cytokines IL‐12 and IL‐18, this protection was reversed when mice received a combined treatment of IL‐33 together with IL‐12 and IL‐18. In summary, our data indicate that IL‐33 treatment induces a population of circulating inflammatory KLRG1hi ILC2s and inhibits type 1 immunity against multiple myeloma. These results argue against therapeutic administration of IL‐33 to myeloma patients.

Innate lymphoid cells and cancer: Role in tumor progression and inhibition

“…The phenotypic and functional alterations of ILC2s are associated with the progression of hematological malignancies [43,[59][60][61]. In acute promyelocytic leukemia (APL), CRTH2 + NKp30 + ILC2s were activated and released IL-13, consequently driving the expansion and the immune suppressive function of IL-13Rα1 + monocytic myeloid-derived suppressor cells (M-MDSCs) (Fig.…”

“…However, emerging findings indicate protumor roles of ILC1s [ 12 , 41 , 42 ]. Of note, besides conventional (Lin − CD127 + CD117 − CRTH2 − NKp46 − ) ILC1s that are expanded in PBMC of hematological malignancies, a unique cluster of CD103 + ILC1‐like cells (ieILC1‐like) have been identified in the TME of a mouse model of solid tumor [ 13 – 16 , 43 , 44 ]. Unlike CD127 + ILC1s that can be converted to ILC3s under stimulation of polarization cytokines, CD103 + ILC1s seems to be refractory to such conversion [ 45 ].…”

“…1C ) [ 60 ]. In animal models of multiple myeloma (MM), ILC2s expressing KLRG1 hi were identified in the liver and spleen of Il2rg −/− Rag2 −/− mice reconstituted with BM ILC2s or IL‐33‐treated WT mice [ 43 ]. In the presence of IL‐33 combined with IL‐12 and IL‐18, KLRG1 hi ILC2s were shown to promote MM progression and inhibit type 1 immunity in Rag‐deficient mice, indicating a subset of ILC2s are deficient in tumor immunosurveillance (Fig.…”

“…In the presence of IL‐33 combined with IL‐12 and IL‐18, KLRG1 hi ILC2s were shown to promote MM progression and inhibit type 1 immunity in Rag‐deficient mice, indicating a subset of ILC2s are deficient in tumor immunosurveillance (Fig. 1C ) [ 43 ]. In anaplastic large cell lymphoma (ALCL), gene expression analysis revealed that primary ALCL showed a gene expression pattern characteristic for ILC3s, implying that a minor subfraction of ALCL might originate from ILC3 [ 61 ].…”

Therapeutic Potential of Innate Lymphoid Cells for Multiple Myeloma Therapy

“…The role of ILC2s in the regulation of MM development and growth was not confirmed in the study. Nevertheless, researchers observed that IL-33 induces the circulating inflammatory population KLRG1h and ILC2s and inhibits type 1 immunity against MM [ 100 ].…”