acute lymphoblastic leukemia; cancer vaccine; CD47
Abstract :
[en] T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis derived from its genetic heterogeneity, which translates to a high chemoresistance. Recently, our workgroup designed thrombospondin-1-derived CD47 agonist peptides and demon- strated their ability to induce cell death in chronic lymphocytic leukemia. Encouraged by these promising results, we evaluated cell death induced by PKHB1 (the first- described serum-stable CD47-agonist peptide) on CEM and MOLT-4 human cell lines (T-ALL) and on one T-murine tumor lymphoblast cell-line (L5178Y-R), also assessing caspase and calcium dependency and mitochondrial membrane potential. Additionally, we evaluated selectivity for cancer cell lines by analyzing cell death and viability of human and murine non-tumor cells after CD47 activation. In vivo, we determined that PKHB1-treatment in mice bearing the L5178Y-R cell line increased leukocyte cell count in peripheral blood and lymphoid organs while recruiting leukocytes to the tumor site. To analyze whether CD47 activation induced immunogenic cell death (ICD), we evaluated damage-associated molecular patterns (DAMP) exposure (calreti- culin, CRT) and release (ATP, heat shock proteins 70 and 90, high-mobility group box 1, CRT). Furthermore, we gave prophylactic antitumor vaccination, determining im- munological memory. Our data indicate that PKHB1 induces caspase-independent and calcium-dependent cell death in leukemic cells while sparing non-tumor murine and human cells. Moreover, our results show that PKHB1 can induce ICD in leukemic cells as it induces CRT exposure and DAMP release in vitro, and prophylactic vaccina- tions inhibit tumor establishment in vivo. Together, our results improve the knowl- edge of CD47 agonist peptides potential as therapeutic tools to treat leukemia
Research Center/Unit :
College of Biology Science, Laboratory of Immunology and Virology, Autonomus University of Nuevo Leon, San Nicolas de los Garza, Mexico CNRS, Biomolecules Laboratory, Superior Normal School, PSL University, Sorbonne University, Paris, France INSERM, UMRS 1138, Sorbonne University, University of Paris Descartes, Sorbonne Paris Cite, Center of Reserch of Cordeliers, Paris, France
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Uscanga-Palomeque, Ashanti
Calvillo-Rodríguez, Kenny
Gómez-Morales, Luis
Lardé, Eva ; Université de Liège - ULiège > Cancer-Metastases Research Laboratory
Karoyan, Philippe
Martínez-Torres, Ana Carolina
Language :
English
Title :
CD47 agonist peptide PKHB1 induces immunogenic cell death in T-cell acute lymphoblastic leukemia cells
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