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Therapy-induced senescence upregulates antigen presentation machinery and triggers anti-tumor immunity in Acute Myeloid Leukemia

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Title:Therapy-induced senescence upregulates antigen presentation machinery and triggers anti-tumor immunity in Acute Myeloid Leukemia
Creators Name:Gilioli, D. and Fusco, S. and Tavella, T. and Giannetti, K. and Conti, A. and Santoro, A. and Carsana, E. and Beretta, S. and Schönlein, M. and Gambacorta, V. and Aletti, F.M. and Carraba, M.G. and Bonini, C. and Ciceri, F. and Merelli, I. and Vago, L. and Schmitt, C.A. and Di Micco, R.
Abstract:Acute myeloid leukemia (AML) is an aggressive hematological malignancy often curable only by using intensive chemotherapy. Nonetheless, resistance/early relapses are frequent, underscoring the need to investigate the molecular events occurring shortly after chemotherapy. Therapy-induced senescence (TIS) is a fail-safe tumor suppressive mechanism that may elicit immune-mediated responses contributing to senescent cell clearance. Yet, TIS functional role in AML eradication and immune surveillance early post-chemotherapy remains ill-defined. By combining transcriptional and cellular-based evaluation of senescence markers in AML patient samples, we found upregulation of senescence-associated genes and interferon gene categories with concomitant induction of HLA class I and class II molecules, pointing to a causal link between TIS and leukemia immunogenicity. Consistently, senescence-competent AML samples activated autologous CD4+ and CD8+ T cells and improved leukemia recognition by both T-cell subsets. Lastly, the anti-leukemic activity of Immune Checkpoint Blockades (ICBs) was enhanced upon senescence engagement in AML. Altogether, our results identify senescence as a potent immune-related anti-leukemic mechanism that may rapidly translate into innovative senescence-based strategies to prevent AML relapse.
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2022.11.17.515658
Date:17 November 2022
Official Publication:https://doi.org/10.1101/2022.11.17.515658

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