B55 alpha/PP2A Limits Endothelial Cell Apoptosis During Vascular Remodeling A Complementary Approach To Disrupt Pathological Vessels?

RATIONALE: How endothelial cells (ECs) migrate and form an immature vascular plexus has been extensively studied. Yet, mechanisms underlying vascular remodeling remain poorly established. A better understanding of these processes may lead to the design of novel therapeutic strategies complementary to current angiogenesis inhibitors. OBJECTIVE: Starting from our previous observations that PP2A (protein phosphatase 2) regulates the HIF (hypoxia-inducible factor)/PHD-2 (prolyl hydroxylase 2)-constituted oxygen machinery, we hypothesized that this axis could play an important role during blood vessel formation, tissue perfusion, and oxygen restoration. METHODS AND RESULTS: We show that the PP2A regulatory subunit B55α is at the crossroad between vessel pruning and vessel maturation. Blood vessels with high B55α counter cell stress conditions and thrive for stabilization and maturation. When B55α is inhibited, ECs cannot cope with cell stress and undergo apoptosis, leading to massive pruning of nascent blood vessels. Mechanistically, we found that the B55α/PP2A complex restrains PHD-2 activity, promoting EC survival in a HIF-dependent manner, and furthermore dephosphorylates p38, altogether protecting ECs against cell stress occurring, for example, during the onset of blood flow. In tumors, EC-specific B55α deficiency induces pruning of immature-like tumor blood vessels resulting in delayed tumor growth and metastasis, without affecting nonpathological vessels. Consistently, systemic administration of a pan-PP2A inhibitor disrupts vascular network formation and tumor progression in vivo without additional effects on B55α-deficient vessels. CONCLUSIONS: Our data underline a unique role of the B55α/PP2A phosphatase complex in vessel remodeling and suggest the use of PP2A-inhibitors as potent antiangiogenic drugs targeting specifically nascent blood vessels with a mode-of-action complementary to VEGF-R (vascular endothelial growth factor receptor)-targeted therapies. Graphical Abstract: A graphical abstract is available for this article.status: publishe

B55PP2A Limits endothelial cell apoptosis during vascular remodeling: a complementary approach to kill pathological vessels?

ABSTRACT Rationale: How endothelial cells (ECs) migrate and form an immature vascular plexus has been extensively studied. Yet, mechanisms underlying vascular remodeling remain poorly established. A better understanding of these processes may lead to the design of novel therapeutic strategies complementary to current angiogenesis inhibitors. Objective: Starting from our previous observations that the PP2A phosphatase regulates the HIF/PHD2- constituted oxygen machinery, we hypothesized that this axis could play an important role during blood vessel formation, tissue perfusion and oxygen restoration. Methods and Results: We show that the regulatory PP2A-phosphatase subunit B55 is at the crossroad between vessel pruning and vessel maturation. Blood vessels with high B55 will counter cell stress conditions and thrive for stabilization and maturation. When B55 is inhibited, ECs cannot cope with cell stress and undergo apoptosis, leading to massive pruning of nascent blood vessels. Mechanistically, we found that the B55/PP2A complex restrains PHD2 activity, promoting EC survival in a HIF-dependent manner, and furthermore dephosphorylates p38, altogether protecting ECs against cell stress occurring, for example, during the onset of blood flow. In tumors, EC-specific B55 deficiency induces pruning of immature-like tumor blood vessels resulting in delayed tumor growth and metastasis, without affecting nonpathological vessels. Consistently, systemic administration of a pan-PP2A inhibitor disrupts vascular network formation and tumor progression in vivo without additional effects on B55-deficient vessels. Conclusions: Our data underline a unique role of the B55/PP2A phosphatase complex in vessel remodeling and suggest the use of PP2A-inhibitors as potent anti-angiogenic drugs targeting specifically nascent blood vessels with a mode-of-action complementary to VEGF(R)-targeted therapies. Keywords: Angiogenesis, B55/PP2A-phosphatase, development, tumor progression, apoptosis, transgenic mode

B55α/PP2A Limits Endothelial Cell Apoptosis During Vascular Remodeling: A Complementary Approach To Disrupt Pathological Vessels?

RATIONALE: How endothelial cells (ECs) migrate and form an immature vascular plexus has been extensively studied. Yet, mechanisms underlying vascular remodeling remain poorly established. A better understanding of these processes may lead to the design of novel therapeutic strategies complementary to current angiogenesis inhibitors. OBJECTIVE: Starting from our previous observations that PP2A (protein phosphatase 2) regulates the HIF (hypoxia-inducible factor)/PHD-2 (prolyl hydroxylase 2)-constituted oxygen machinery, we hypothesized that this axis could play an important role during blood vessel formation, tissue perfusion, and oxygen restoration. METHODS AND RESULTS: We show that the PP2A regulatory subunit B55α is at the crossroad between vessel pruning and vessel maturation. Blood vessels with high B55α counter cell stress conditions and thrive for stabilization and maturation. When B55α is inhibited, ECs cannot cope with cell stress and undergo apoptosis, leading to massive pruning of nascent blood vessels. Mechanistically, we found that the B55α/PP2A complex restrains PHD-2 activity, promoting EC survival in a HIF-dependent manner, and furthermore dephosphorylates p38, altogether protecting ECs against cell stress occurring, for example, during the onset of blood flow. In tumors, EC-specific B55α deficiency induces pruning of immature-like tumor blood vessels resulting in delayed tumor growth and metastasis, without affecting nonpathological vessels. Consistently, systemic administration of a pan-PP2A inhibitor disrupts vascular network formation and tumor progression in vivo without additional effects on B55α-deficient vessels. CONCLUSIONS: Our data underline a unique role of the B55α/PP2A phosphatase complex in vessel remodeling and suggest the use of PP2A-inhibitors as potent antiangiogenic drugs targeting specifically nascent blood vessels with a mode-of-action complementary to VEGF-R (vascular endothelial growth factor receptor)-targeted therapies. Graphical Abstract: A graphical abstract is available for this article

B55α/PP2A Limits Endothelial Cell Apoptosis During Vascular Remodeling: A Complementary Approach To Kill Pathological Vessels?

Rationale: How endothelial cells (ECs) migrate and form an immature vascular plexus has been extensively studied. Yet, mechanisms underlying vascular remodeling remain poorly established. A better understanding of these processes may lead to the design of novel therapeutic strategies complementary to current angiogenesis inhibitors. Objective: Starting from our previous observations that the PP2A phosphatase regulates the HIF/PHD2-constituted oxygen machinery, we hypothesized that this axis could play an important role during blood vessel formation, tissue perfusion and oxygen restoration. Methods and Results: We show that the regulatory PP2A-phosphatase subunit B55? is at the crossroad between vessel pruning and vessel maturation. Blood vessels with high B55? will counter cell stress conditions and thrive for stabilization and maturation. When B55? is inhibited, ECs cannot cope with cell stress and undergo apoptosis, leading to massive pruning of nascent blood vessels. Mechanistically, we found that the B55?/PP2A complex restrains PHD2 activity, promoting EC survival in a HIF-dependent manner, and furthermore dephosphorylates p38, altogether protecting ECs against cell stress occurring, for example, during the onset of blood flow. In tumors, EC-specific B55? deficiency induces pruning of immature-like tumor blood vessels resulting in delayed tumor growth and metastasis, without affecting non-pathological vessels. Consistently, systemic administration of a pan-PP2A inhibitor disrupts vascular network formation and tumor progression in vivo without additional effects on B55?-deficient vessels. Conclusions: Our data underline a unique role of the B55?/PP2A phosphatase complex in vessel remodeling and suggest the use of PP2A-inhibitors as potent anti-angiogenic drugs targeting specifically nascent blood vessels with a mode-of-action complementary to VEGF(R)-targeted therapies

PlexinA4 mediates cytotoxic T cell trafficking and exclusion in cancer

Cytotoxic T cell (CTL) infiltration of the tumor carries the potential to limit cancer progression, but their exclusion by the immunosuppressive tumor microenvironment hampers the efficiency of immunotherapy. Here, we show that expression of the axon guidance molecule PlexinA4 (Plxna4) in CTLs, especially in effector/memory CD8+ T cells, is induced upon T-cell activation, sustained in the circulation, but reduced when entering the tumor bed. Therefore, we deleted Plxna4 and observed that Plxna4-deficient CTLs acquired improved homing capacity to the lymph nodes and to the tumor, as well as increased proliferation, both achieved through enhanced Rac1 activation. Mice with stromal or hematopoietic Plxna4 deletion exhibited enhanced CTL infiltration and impaired tumor growth. In a melanoma model, adoptive transfer of CTLs lacking Plxna4 prolonged survival and improved therapeutic outcome, which was even stronger when combined with anti-PD-1 treatment. PLXNA4 abundance in circulating CTLs was augmented in melanoma patients versus healthy volunteers but decreased after the first cycle of anti-PD-1, alone or in combination with anti-CTLA-4, in those patients showing complete or partial response to the treatment. Altogether, our data suggest that PlexinA4 acts as a "checkpoint", negatively regulating CTL migration and proliferation through cell autonomous mechanisms independent of the interaction with host-derived PlexinA4 ligands semaphorins. These findings pave the way towards PlexinA4-centric immunotherapies and propose PlexinA4 detection in circulating CTLs as a potential way to monitor the response to immune checkpoint blockade in metastatic melanoma patients