TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies

Courau, Tristan; Nehar-Belaid, Djamel; Flórez, Laura; Levacher, Béatrice; Vazquez, Thomas; Brimaud, Faustine; Bellier, Bertrand; Klatzmann, David

doi:10.1172/jci.insight.85974

Cited by 91 publications

(73 citation statements)

References 58 publications

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“…VEGF down‐modulation resulted in a decrease in Tregs and MDSC and an increased effector T‐cell activation in tumor infiltrates. Together, these events restored tumor sensitivity to treatment with antibodies against the checkpoint inhibitors PD‐1 and CTLA‐4 (Courau et al , ).…”

Section: Discussionmentioning

confidence: 98%

VEGF blockade enhances the antitumor effect of BRAF ^V ^600E inhibition

et al. 2016

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The development of resistance remains a major obstacle to long‐term disease control in cancer patients treated with targeted therapies. In BRAF‐mutant mouse models, we demonstrate that although targeted inhibition of either BRAF or VEGF initially suppresses the growth of BRAF‐mutant tumors, combined inhibition of both pathways results in apoptosis, long‐lasting tumor responses, reduction in lung colonization, and delayed onset of acquired resistance to the BRAF inhibitor PLX4720. As well as inducing tumor vascular normalization and ameliorating hypoxia, this approach induces remodeling of the extracellular matrix, infiltration of macrophages with an M1‐like phenotype, and reduction in cancer‐associated fibroblasts. At the molecular level, this therapeutic regimen results in a de novo transcriptional signature, which sustains and explains the observed efficacy with regard to cancer progression. Collectively, our findings offer new biological rationales for the management of clinical resistance to BRAF inhibitors based on the combination between BRAFV 600E inhibitors with anti‐angiogenic regimens.

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Section: Discussionmentioning

confidence: 98%

VEGF blockade enhances the antitumor effect of BRAF ^V ^600E inhibition

et al. 2016

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“…Inhibition of these pathways may improve cancer immunity in the tumor microenvironment, because VEGFRs and FGFRs signals play suppressive roles in immune responses. [29][30][31][32] In particular, VEGF is a well-characterized immunosuppressive factor. 33 Accumulating evidence suggests that VEGF inhibits the maturation and activity of immune cell populations such as T cells and DCs, but it remains unknown whether inhibition of VEGF signaling alone is sufficient to activate anticancer immunity.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1‐6 hepatocellular carcinoma model

et al. 2018

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Angiogenesis inhibitors such as lenvatinib and sorafenib, and an immune checkpoint inhibitor (ICI), nivolumab, are used for anticancer therapies against advanced hepatocellular carcinoma (HCC). Combination treatments comprising angiogenesis inhibitors plus ICIs are promising options for improving clinical benefits in HCC patients, and clinical trials are ongoing. Here, we investigated the antitumor and immunomodulatory activities of lenvatinib (a multiple receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 1‐3, fibroblast growth factor receptor 1‐4, platelet‐derived growth factor receptor α, KIT and RET) and the combined antitumor activity of lenvatinib plus anti‐programmed cell death 1 (PD‐1) antibody in the Hepa1‐6 mouse HCC syngeneic model. We found that the antitumor activities of lenvatinib and sorafenib were not different in immunodeficient mice, but lenvatinib showed more potent antitumor activity than sorafenib in immunocompetent mice. The antitumor activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8+ T cell depletion. Treatment with lenvatinib plus anti‐PD‐1 antibody resulted in more tumor regression and a higher response rate compared with either treatment alone in immunocompetent mice. Single‐cell RNA sequencing analysis demonstrated that treatment with lenvatinib with or without anti‐PD‐1 antibody decreased the proportion of monocytes and macrophages population and increased that of CD8+ T cell populations. These data suggest that lenvatinib has immunomodulatory activity that contributes to the antitumor activity of lenvatinib and enhances the antitumor activity in combination treatment with anti‐PD‐1 antibody. Combination treatment of lenvatinib plus anti‐PD‐1 antibody therefore warrants further investigation against advanced HCC.

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“…In vivo and in vitro analyses have shown that VEGF released from the tumor microenvironment stimulates the mobilization of MDSCs from the bone marrow to the peripheral blood, thus leading to increased MDSC levels in the peripheral blood. In addition, VEGF contributes to the selective accumulation of MDSCs within tumor sites [114]. Therefore, VEGF may not only promote tumor growth but also participate in a suppressive process that limits antitumor immunity [115].…”

Section: Bevacizumabmentioning

confidence: 99%

Myeloid-derived suppressor cells—new and exciting players in lung cancer

et al. 2020

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Lung cancer (LC) is the leading cause of cancer-related death worldwide due to its late diagnosis and poor outcomes. As has been found for other types of tumors, there is increasing evidence that myeloid-derived suppressor cells (MDSCs) play important roles in the promotion and progression of LC. Here, we briefly introduce the definition of MDSCs and their immunosuppressive functions. We next specifically discuss the multiple roles of MDSCs in the lung tumor microenvironment, including those in tumor growth and progression mediated by inhibiting antitumor immunity, and the associations of MDSCs with a poor prognosis and increased resistance to chemotherapy and immunotherapy. Finally, we also discuss preclinical and clinical treatment strategies targeting MDSCs, which may have the potential to enhance the efficacy of immunotherapy.

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TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies

Abstract: International audienc

Cited by 91 publications

References 58 publications

VEGF blockade enhances the antitumor effect of BRAF ^V ^600E inhibition

VEGF blockade enhances the antitumor effect of BRAF ^V ^600E inhibition

Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1‐6 hepatocellular carcinoma model

Myeloid-derived suppressor cells—new and exciting players in lung cancer

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TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies

Abstract: International audienc

Cited by 91 publications

References 58 publications

VEGF blockade enhances the antitumor effect of BRAF V 600E inhibition

VEGF blockade enhances the antitumor effect of BRAF V 600E inhibition

Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1‐6 hepatocellular carcinoma model

Myeloid-derived suppressor cells—new and exciting players in lung cancer

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Product

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VEGF blockade enhances the antitumor effect of BRAF ^V ^600E inhibition

VEGF blockade enhances the antitumor effect of BRAF ^V ^600E inhibition