Unraveling the dynamic of immuno-vascular cross-talk during glioma progression.
Vascular dysmorphia and massive accumulation of tumour-supportive macrophages are hallmarks of the immunosuppressed Glioblastoma (GBM) microenvironment (1). Both processes promote tumour progression and hinder delivery of existing therapeutics to combat GBM. On the one hand, non-uniform oxygen delivery via dysmorphic and leaky tumour vessels leads to hypoxia, which upregulates angiogenic factors and thereby creates a vicious cycle that prevents delivery of cytotoxic agents to kill tumour cells. On the other hand, infiltration of immunosuppressive myeloid cells combined with the minimal recruitment of T cells limits the success of currently available T cell-oriented immunotherapies. The axon guidance factor Slit2 has recently been described as a novel requisite pro-angiogenic factor in mice, as it has been shown that VEGF cannot induce angiogenesis in the absence of Slit-Robo signaling (2). Following these results, we aimed at investigating the role of Slit-Robo pathway over glioma progression in the different cell compartments of the tumor. Our study has shown that the secreted guidance factor Slit2 drives glioma progression by inducing blood vessel dysmorphia and recruitment of immunosuppressive myeloid cells, and by depriving the tumour microenvironment of cytotoxic T cells. In vivo longitudinal analysis of a syngeneic mouse GBM model showed that Slit2 depletion in tumour cells re-educated the tumour stroma and reduced glioma growth by inducing vasculature normalization and accumulation of cytotoxic immune cells (3). Therapeutically, Slit2 neutralization by systemic administration of a ligand trap shifted the tumour microenvironment and resulted in a robust blockade of mouse GBM progression that was further enhanced by chemotherapy.
These data reveal Slit2 as a novel regulator of the GBM microenvironment and a potential therapeutic target to treat brain tumours.
References:
1. Mathivet T; Bouleti C; Van Woensel M; Stanchi F; Verschuere T; Phng LK; Dejaegher J; Balcer M; Matsumoto K; Georgieva P; Belmans J; Sciot R; Stockmann C, Mazzone M; De Vleeschouwer S; Gerhardt H. Dynamic stroma reorganization drives blood vessel dysmorphia during glioma growth. EMBO Mol Med. 2017
2. Rama N*, Dubrac A*, Mathivet T, Ní Chárthaigh RA, Genet G, Cristofaro B, Pibouin-Fragner L, Ma L, Eichmann A, Chédotal A. Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization. Nat Med, 2015.
3. Geraldo LH, Xu Y, Jacob L, Pibouin-Fragner L, Rao R, Maïssa N, Verreault M, Lemaire N, Knosp C, Lesaffre C, Daubon T, Dejaegher J, Solie L, Rudewicz J, Viel T, Tavitian B, De Vleeschouwer S, Sanson M, Bikfalvi A, Idbaih A, Lu QR, Lima FR, Thomas JL, Eichmann A, Mathivet T. SLIT2/ROBO signaling in tumor-associated microglia/macrophages drives glioblastoma immunosuppression and vascular dysmorphia. J Clin Invest, 2021
Séminaire retransmis en visioconférence :
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