VEGFA/VEGFR2-targeted therapies prevent the VEGFA-induced proliferation of regulatory T cells in cancer

Terme, Magali; Tartour, Éric; Taı̈eb, Julien

doi:10.4161/onci.25156

Cited by 37 publications

(23 citation statements)

References 10 publications

(11 reference statements)

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“…In addition, VEGF can limit T cell extravasation and induce expansion of Treg populations, thereby further enhancing the immunosuppressive state. 34,[54][55][56] It is, therefore, reasonable to expect that inhibition of the VEGF/VEGFR-2 axis would reverse tumor-mediated immunosuppression or enhance the effects of immunostimulatory antitumor therapies. 31,34,36 In contrast with these observations, however, experimental data show that anti-angiogenic therapy also mobilizes MDSC, which in turn can limit the therapeutic benefit of anti-angiogenic therapy, 26,29,31 and in certain tumor models may even exacerbate metastatic progression.…”

Section: Discussionmentioning

confidence: 99%

Arginase inhibition suppresses lung metastasis in the 4T1 breast cancer model independently of the immunomodulatory and anti-metastatic effects of VEGFR-2 blockade

et al. 2017

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Tumor angiogenesis promotes tumor growth and metastasis. Anti-angiogenic therapy in combination with chemotherapy is used for the treatment of metastatic cancers, including breast cancer but therapeutic benefits are limited. Mobilization and accumulation of myeloid-derived suppressor cells (MDSC) during tumor progression and therapy have been implicated in metastasis formation and resistance to antiangiogenic treatments. Here, we used the 4T1 orthotopic syngenic mouse model of mammary adenocarcinoma to investigate the effect of VEGF/VEGFR-2 axis inhibition on lung metastasis, MDSC and regulatory T cells (Tregs). We show that treatment with the anti-VEGFR-2 blocking antibody DC101 inhibits primary tumor growth, angiogenesis and lung metastasis. DC101 treatment had no effect on MDSC mobilization, but partially attenuated the inhibitory effect of mMDSC on T cell proliferation and decreased the frequency of Tregs in primary tumors and lung metastases. Strikingly, DC101 treatment induced the expression of the immune-suppressive molecule arginase I in mMDSC. Treatment with the arginase inhibitor N v -hydroxy-nor-Arginine (Nor-NOHA) reduced the inhibitory effect of MDSC on T cell proliferation and inhibited number and size of lung metastasis but had little or no additional effects in combination with DC101.In conclusion, DC101 treatment suppresses 4T1 tumor growth and metastasis, partially reverses the inhibitory effect of mMDSC on T cell proliferation, decreases Tregs in tumors and increases arginase I expression in mMDSC. Arginase inhibition suppresses lung metastasis independently of DC101 effects. These observations contribute to the further characterization of the immunomodulatory effect of anti-VEGF/VEGFR2 therapy and provide a rationale to pursue arginase inhibition as potential anti-metastatic therapy.

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Section: Discussionmentioning

confidence: 99%

Arginase inhibition suppresses lung metastasis in the 4T1 breast cancer model independently of the immunomodulatory and anti-metastatic effects of VEGFR-2 blockade

et al. 2017

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“…It is well known that TGF-β and VEGF-A are potent immunosuppressive factors that drive the expansion of regulatory T-cells and myeloid-derived suppressor cells (37). Moreover, platelets also contain proteins such as thrombospondin-1 (TSP-1) and CD40L.…”

Section: Figure 3 Sequential Changes In Blood Sample Values At 6 H mentioning

confidence: 99%

Role for Neutrophil Extracellular Traps (NETs) and Platelet Aggregation in Early Sepsis-induced Hepatic Dysfunction

Sakurai

Miyashita

Okazaki

et al. 2017

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Abstract. Background Sepsis is a clinical syndrome of systemic inflammatory responses arising from an infectious process with a presumed or known focus (1, 2). Severe sepsis, defined as sepsis with acute organ dysfunction, is associated with high morbidity and mortality rates (3). Inflammation and coagulation play pivotal roles in the pathogenesis of sepsis (4, 5). Sepsis-induced multiple organ failure (MOF) has numerous causes, such as various types of shock, adult respiratory distress syndrome (ARDS), and disseminated intravascular coagulation (DIC) (6). Gando et al. (7) reported that DIC is frequently associated with systemic inflammatory response syndrome (SIRS; 83%) and that such patients have a high mortality rate (63%). Ogura et al. (4) evaluated coagulation activity, organ dysfunction, and SIRS in critically-ill patients with thrombocytopenia and examined the balance between coagulopathy and systemic inflammation. In critically-ill patients with thrombocytopenia, they found that coagulopathy and organ dysfunction progressed with a significant mutual correlation, depending on the increase in SIRS scores. Thus, SIRSassociated coagulopathy may play a critical role in inducing organ dysfunction after severe insult. 1051This article is freely accessible online.Correspondence to: Tomoharu Miyashita,

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“…T‐cell tolerance through natural or induced pathways of self‐tolerance generation appears to be the most difficult one and this represents a significant challenge to successful cancer immunotherapy. To achieve an effective anti‐tumour response, therapeutic vaccines must be capable of overcoming or reversing T‐cell tolerance to tumour antigens whether it is via naturally occurring CD4 + CD25 + Treg cells or by induced Treg cells (induced from CD4 + CD25 − cells) . We have shown that tumour‐specific CTL generated in vitro from total PBL declined within 2–3 weeks with a concomitant expansion of suppressor type CD4 + cells .…”

Section: The Possibilities To Circumvent Treg Cell‐based Constraintsmentioning

confidence: 90%

“…Anti‐angiogenic agents that are used to treat solid tumours have effects on tumour endothelial cells as well as on immune cells. Targeting the VEGFA/VEGF receptor 2 (VEGFR2) signalling pathway reduces the proportion of Treg cells in mouse as well as human colorectal cancer because it inhibits tumour‐induced Treg cell proliferation . Similarly it has been found that the TLR7/8L:CL097 could simultaneously activate CD8 + T cells, B cells and natural killer cells and block Treg cell suppression of T cells and B cells …”

Section: The Possibilities To Circumvent Treg Cell‐based Constraintsmentioning

confidence: 99%

Manipulation of regulatory T cells and antigen‐specific cytotoxic T lymphocyte‐based tumour immunotherapy

2015

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The most potent killing machinery in our immune system is the cytotoxic T lymphocyte (CTL). Since the possibility for self-destruction by these cells is high, many regulatory activities exist to prevent autoimmune destruction by these cells. A tumour (cancer) grows from the cells of the body and is tolerated by the body's immune system. Yet, it has been possible to generate tumour-associated antigen (TAA) -specific CTL that are also self-antigen specific in vivo, to achieve a degree of therapeutic efficacy. Tumour-associated antigen-specific T-cell tolerance through pathways of self-tolerance generation represents a significant challenge to successful immunotherapy. These cells are to be termed as peripherally induced Treg (pTreg) cells. In vitro-induced Treg cells with suppressor function should be termed as iTreg. These different Treg cells differ in their requirements for activation and in their mode of action. The current challenges are to determine the degree of specificity of these Treg cells in recognizing the same TAA as the CTL population and to circumvent their regulatory constraints so as to achieve robust CTL responses against cancer.

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VEGFA/VEGFR2-targeted therapies prevent the VEGFA-induced proliferation of regulatory T cells in cancer

Cited by 37 publications

References 10 publications

Arginase inhibition suppresses lung metastasis in the 4T1 breast cancer model independently of the immunomodulatory and anti-metastatic effects of VEGFR-2 blockade

Arginase inhibition suppresses lung metastasis in the 4T1 breast cancer model independently of the immunomodulatory and anti-metastatic effects of VEGFR-2 blockade

Role for Neutrophil Extracellular Traps (NETs) and Platelet Aggregation in Early Sepsis-induced Hepatic Dysfunction

Manipulation of regulatory T cells and antigen‐specific cytotoxic T lymphocyte‐based tumour immunotherapy

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