1. The immune checkpoint ICOSLG is a relapse-predicting biomarker and therapeutic target in infant t(4;11) acute lymphoblastic leukemia
- Author
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Marius Külp, Anna Lena Siemund, Patrizia Larghero, Alissa Dietz, Julia Alten, Gunnar Cario, Cornelia Eckert, Aurelie Caye-Eude, Helene Cavé, Michela Bardini, Giovanni Cazzaniga, Paola De Lorenzo, Maria Grazia Valsecchi, Laura Diehl, Bonig Halvard, Claus Meyer, Rolf Marschalek, Kulp, M, Siemund, A, Larghero, P, Dietz, A, Alten, J, Cario, G, Eckert, C, Caye-Eude, A, Cave, H, Bardini, M, Cazzaniga, G, De Lorenzo, P, Valsecchi, M, Diehl, L, Bonig, H, Meyer, C, and Marschalek, R
- Subjects
History ,Polymers and Plastics ,Health science ,Immunology ,Business and International Management ,Industrial and Manufacturing Engineering ,Cancer - Abstract
The most frequent genetic aberration leading to infant ALL (iALL) is the chromosomal translocation t(4;11), generating the fusion oncogenes KMT2A:AFF1 and AFF1:KMT2A, respectively. KMT2A-r iALL displays a dismal prognosis through high relapse rates and relapse-associated mortality. Relapse occurs frequently despite ongoing chemotherapy and without the accumulation of secondary mutations. A rational explanation for the observed chemo-resistance and satisfactory treatment options remain to be elucidated. We found that elevated ICOSLG expression level at diagnosis was associated with inferior event free survival (EFS) in a cohort of 43 patients with t(4;-11) iALL and that a cohort of 18 patients with iALL at relapse displayed strongly increased ICOSLG expression. Furthermore, co-culturing t(4;11) ALL cells (ICOSLGhi) with primary T-cells resulted in the development of Tregs. This was impaired through treatment with a neutralizing ICOSLG antibody. These findings imply ICOSLG (1) as a relapse-predicting biomarker, and (2) as a therapeutic target involved in a potential immune evasion relapse-mechanism of infant t(4;11) ALL.
- Published
- 2022