IL-18 and VEGF-A trigger type 2 innate lymphoid cell accumulation and pro-tumoral function in chronic myeloid leukemia
Benedetta Fiordi,
Valentina Salvestrini,
Gabriele Gugliotta,
Fausto Castagnetti,
Antonio Curti,
Daniel E. Speiser,
Emanuela Marcenaro,
Camilla Jandus,
Sara Trabanelli
Affiliations
Benedetta Fiordi
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
Valentina Salvestrini
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology « Seràgnoli », Bologna, Italy
Gabriele Gugliotta
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology « Seràgnoli », Bologna, Italy
Fausto Castagnetti
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology « Seràgnoli », Bologna, Italy
Antonio Curti
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology « Seràgnoli », Bologna, Italy
Daniel E. Speiser
Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne, Epalinges, Switzerland
Emanuela Marcenaro
Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy
Camilla Jandus
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
Sara Trabanelli
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
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 (ILC), whose role in cancer has recently emerged. Three ILC subsets are identified based on transcriptional profiles and cytokine secretion. We observed that interleukin 18 (IL-18) and vascular endothelial growth factor A (VEGF-A) are increased in CML patients’ sera and that ILC2 are enriched in CML PB and BM. We found that IL-18 drives ILC2 proliferation and that CML ILC2 highly express CXCR4 and CXCR7 BM-homing receptors, potentially explaining their enrichment in PB and BM, respectively. Next, we showed that ILC2 are hyper-activated through a tumor-derived VEGF-Adependent 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 ILC2 was disrupted upon tyrosine kinase inhibitor treatment, normalizing the levels of all these players in CML patients responding to therapy. Overall, our study uncovers the involvement of ILC2 in CML progression, mediated by VEGF-A and IL-18.
