IL-18 and VEGF-A trigger type 2 innate lymphoid cell accumulation and pro-tumoral function in chronic myeloid leukemia
SUMMARY
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, the authors of this article 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. They observed that IL-18 and VEGF-A are increased in CML patients' sera and that ILC2s are enriched in CML PB and BM. They 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, they showed that ILC2s are hyper-activated through a tumour-derived VEGF-A-dependent mechanism, which leads to higher IL-13 secretion. In response to IL-13, leukemic cells increase their clonogenic capacity. Finally, they 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, this study uncovers the involvement of ILC2s in CML progression, mediated by VEGF-A and IL-18.
This work was founded by the SNSF, the Dr Henri Dubois-Ferrière Dinu Lipatti Foundation, AIRC, Compagnia di San Paolo and ISREC PhD Scholarship.
Full article: https://haematologica.org/article/view/haematol.2022.282140
Why is it important?
Chronic myeloid leukaemia (CML) is rare and was the first cancer clearly linked to a chromosomal abnormality. Although the introduction of tyrosine kinase inhibitors (TKIs) (e.g., imatinib, dasatinib, nilotinib, ponatinib) has greatly changed the CML treatment landscape, up to 10% of patients remain unresponsive to treatment due to the development of treatment resistance. The only curative option for these patients remains stem cell transplantation, which leads to complications such as graft-versus-host disease or graft failure, among others. For these reasons, research in CML is needed to provide new therapies for TKI-resistant patients.
The authors of this article focused on the innate lymphoid cell (ILC) family, a recently described group of immune cells that have been shown to be involved in different biological processes, both physiological, such as antimicrobial responses, tissue homeostasis or lymphoid organ development, and pathological, such as autoimmunity and cancer. Previous evidence showed that ILCs are altered in several solid tumours and haematological malignancies.
The goal of this research was to understand whether ILCs are dysregulated in CML and to characterise their role in this disease. The authors show a novel mechanism in CML in which IL-18 and tumour-derived VEGF-A activate ILC2, leading to increased ILC2 proliferation and IL-13 secretion, which in turn promotes tumorigenesis. The frequency of ILC2 correlates with the aggressiveness of the disease, as already shown for other cancers. Moreover, the authors found a significant decrease in the frequency of ILC1 in CML patients at disease onset that recovered after treatment with TKI. This finding suggests that partial loss of ILC1 may play a role in the establishment of the pro-tumour microenvironment and that its recovery may contribute to the favourable outcome of TKI treatment. These results together open the door to the discovery of new immunotherapies for this type of tumour.