IL-18 and VEGF-A trigger type 2 innate lymphoid cell accumulation and pro-tumoral function in chronic myeloid leukemia

Abstract

Chronic Myeloid Leukemia (CML) is a hematologic malignancy associated to an unregulated growth of myeloid cells in Bone Marrow (BM) and Peripheral Blood (PB), characterized by the BCR-ABL1 translocation. Given the known cytokine impairment in the leukemic niche of CML, we investigated the impact of this microenvironmental dysregulation on Innate Lymphoid Cells (ILCs), whose role in cancer has recently emerged. Three ILC subsets are identified based on transcriptional profiles and cytokine secretion. We observed that IL-18 and VEGF-A are increased in CML patients’ sera and that ILC2s are enriched in CML PB and BM. We found that IL-18 drives ILC2 proliferation and that CML ILC2s highly express CXCR4 and CXCR7 BM-homing receptors, potentially explaining their enrichment in PB and BM, respectively. Next, we showed that ILC2s are hyper-activated through a tumor-derived VEGF-A-dependent mechanism, which leads to higher IL-13 secretion. In response to IL-13, leukemic cells increase their clonogenic capacity. Finally, we discovered that the pro-tumoral axis involving VEGF-A, IL-18 and ILC2s was disrupted upon Tyrosine Kinase Inhibitors’ (TKIs) treatment, normalizing the levels of all these players in CML patients responding to therapy. Overall, our study uncovers the involvement of ILC2s in CML progression, mediated by VEGF-A and IL-18.

IL-18, a therapeutic target for immunotherapy boosting, promotes temozolomide chemoresistance via the PI3K/AKT pathway in glioma

“…Here, we focused on IL-18, which was formerly recognized as IFN-γ-inducing cytokine and was later recognized as a proin ammatory cytokine that induces IFN-γ.25 IL-18 is correlated with a poor prognosis in diverse tumors, involving pancreatic carcinoma, glioma, mammary carcinoma, stomach carcinoma, and multiple myeloma. [9][10][11][12][13][14][15] Additionally, IL-18 level of the serum is upregulated in individuals with glioma. 26 Our study presented that IL-18 was abundantly detected in TR cells and microenvironment.…”

“…8 IL-18 is abundantly expressed in many tumor tissues, promoting cancer progression, involving glioma, pancreatic carcinoma, breast carcinoma, stomach carcinoma, and multiple myeloma. [9][10][11][12][13][14][15] Recent studies indicate that IL-18 contributed to tumor chemoresistance. 16,17 However, the in-depth role of IL-18 in chemoresistance of glioma remains unclear.…”