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

Infant proB ALL is mainly caused by the chromosomal translocation t(4;11), generating the fusion oncogenes KMT2A::AFF1 and AFF1::KMT2A. Generally, KMT2A-rearranged iALL is characterized by dismal outcome due to high relapse incidences and relapse-associated mor-tality. Relapse appears despite continuous chemotherapy but without selection of secondary mutations. Therefore, the mechanism of therapy failure and relapse formation remains to be elucidated. Here, we present first evidence that ALL cells overexpressing ICOSLG are strongly correlated with relapse formation and poor event-free survival (EFS). ICOSLG ex-pression is transcriptionally regulated by the IRX1-EGR3 axis, and co-culture of ICOSLG-expressing t(4;11) ALL cells with primary T-lymphocytes led to an increase of regulatory T-cells (Tregs). A commercial α-ICOSLG antibody is available that impairs this mechanism. We propose that these Tregs potentially protect leukemia initiating cells in their bone marrow niche. In summary, our data point to ICOSLG as a relapse-predicting biomarker and therapeutic target, involved in an immune evasion relapse-mechanism in infant t(4;11) proB-ALL.

Publication History

Article published online:
17 May 2022