The immune checkpoint ICOSLG is a relapse-predicting biomarker and therapeutic target in infant t(4;11) acute lymphoblastic leukemia

• Published in: iScience Vol. 25; no. 7; p. 104613
• Main Authors: Külp, Marius, Siemund, Anna Lena, Larghero, Patrizia, Dietz, Alissa, Alten, Julia, Cario, Gunnar, Eckert, Cornelia, Caye-Eude, Aurélie, Cavé, Hélène, Bardini, Michela, Cazzaniga, Giovanni, De Lorenzo, Paola, Valsecchi, Maria Grazia, Diehl, Laura, Bonig, Halvard, Meyer, Claus, Marschalek, Rolf
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 15.07.2022; Elsevier
• Subjects: Cancer; Health sciences; Immunology; Health sciences; Immunology; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.104613

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. [Display omitted] •Early growth response 3 (EGR3) is a direct transactivator of the immune checkpoint gene ICOSLG•high ICOSLG expression at diagnosis is predictive for ALL relapse•EGR3 and ICOSLG expressions are relapse-associated•expression of ICOSLG on t(4;11) ALL cells leads to the rapid expansion of Tregs Health sciences; Immunology; Cancer