T-cell acute lymphoblastic leukemia progression is supported by inflammatory molecules including Hepatocyte Growth factor
BackgroundT-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disorder characterized by an increased proliferation of immature T lymphocytes precursors. T-ALL treatment includes chemotherapy with strong side effects, and patients that undergo relapse display poor prognosis. Although cell-intrinsic oncogenic pathways are well-studied, the tumor microenvironment, like inflammatory cellular and molecular components is less explored in T-ALL. We sought to determine the composition of the inflammatory microenvironment induced by T-ALL, and its role in T-ALL progression. MethodsTwo mouse T-ALL cell models were injected into immunocompetent mice. We used anti-Ly6G, and clodronate liposomes to suppress neutrophils and phagocytes, respectively. 5- (N-ethylcarboxamido)adenosine (NECA), an agonist of adenosine receptors was used to decrease inflammatory molecules secretion. FindingsWe show that T-ALLs enhance blood neutrophils and resident monocytes, accompanied with a plasmatic acute secretion of inflammatory molecules. Depleting neutrophils or resident monocytes does not modulate plasmatic inflammatory molecule secretion and mice survival. However, inhibiting the secretion of inflammatory molecules by microenvironment with NECA diminishes T-ALL progression enhancing mouse survival. We uncovered Hepatocyte Growth Factor (HGF), T-ALL-driven and the most decreased molecule with NECA, as a potential therapeutic target in T-ALL. InterpretationAltogether, we identified a signature of inflammatory molecules that can potentially be involved in T-ALL evolution and uncovered HGF as a new potential therapeutic target. FundingsThe work was supported by CEA, Inserm, Universite Paris-Saclay and Universite Paris-Cite, la Recherche contre le Cancer (ARC) and Hope of Princess Manon charity. The LSHL team is labellised by Ligue Nationale Contre le Cancer. Research in contextO_ST_ABSEvidence before this studyC_ST_ABST-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and lethal hematologic malignancy accounting for about 15% of pediatric and 25% of adult ALL. T-ALL originates from a block of differentiation and uncontrolled proliferation of immature T cells. Current chemotherapies provide an overall 5 years survival higher than 90% in children and of about 50% in adults. Both pediatric and adult relapses have a very poor outcome with resistance to treatment. Therefore, the identification of molecular targets and the development of new specific therapies are major goals to improve treatment success, and one way to reach this goal is to have a better understanding the dialog between T-ALL cells and their microenvironment. Cellular and molecular actors in the microenvironment have been identified to impact several types of leukemia. Recently, the supportive role of myeloid cells has been described in T-ALL. Moreover, interactions between receptors and ligands such as DL1, IL-18, IL-7, IGF1 and CXCL12 sustain proliferation, survival or initiation of T-ALL. However, the composition and the contribution of the inflammatory microenvironment that may broadly help T-ALL progression still remains poorly explored. Added value of this studyThe study, utilizing NOTCH1 and TAL1/LMO1-driven mouse T-ALL models, reveals that T-ALL induces an inflammatory microenvironment characterized by increased levels of blood neutrophils, resident monocytes, and plasmatic inflammatory molecules. Targeting molecular microenvironment with the non-selective adenosine receptor agonist NECA drastically decreases T-ALL progression and prolongs mice survival. This study further identifies hepatocyte growth factor (HGF), a known regulator of proliferation and migration of tumor cells, as a putative supportive and targetable factor in T-ALL. Implications of all the available evidenceIn this study, evidence linking T-ALL and inflammatory microenvironment is provided. These data extend our understanding of the biological function of inflammatory microenvironment in T-ALL progression, and open to the targeting of the inflammatory microenvironment, and more specifically HGF/cMet signaling in T-ALL. Such targeted therapeutic approach could be added to current treatments to improve patient outcome.