Dataset Information

Dual Transforming Growth Factor-? and Programmed Death-1 Blockade: A Strategy for Immune-Excluded Tumors?

ABSTRACT: Tumors that elude infiltration by CD8+ T lymphocytes are particularly resistant to multiple forms of treatment, including immune checkpoint blockade. Stromal transforming growth factor (TGF)-? appears to play a key role in this process, potentially constituting a target for novel combinatorial regimens tackling immune-excluded neoplasms.

SUBMITTER: Vanpouille-Box C

PROVIDER: S-EPMC5972064 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Dual Transforming Growth Factor-β and Programmed Death-1 Blockade: A Strategy for Immune-Excluded Tumors?

Vanpouille-Box Claire C Formenti Silvia C SC

Trends in immunology 20180326 6

Tumors that elude infiltration by CD8<sup>+</sup> T lymphocytes are particularly resistant to multiple forms of treatment, including immune checkpoint blockade. Stromal transforming growth factor (TGF)-β appears to play a key role in this process, potentially constituting a target for novel combinatorial regimens tackling immune-excluded neoplasms. ...[more]

PMID: 29598848

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Project description:Background and aimsActivation of the antitumor immune response using programmed death receptor-1 (PD-1) blockade showed benefit only in a fraction of patients with hepatocellular carcinoma (HCC). Combining PD-1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of patients with HCC who respond to treatment, but the mechanism of this interaction is unknown.Approach and resultsWe recapitulated these clinical outcomes using orthotopic-grafted or induced-murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR-2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti-PD-1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti-PD-1/VEGFR-2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing cluster of differentiation 8-positive (CD8+ ) cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor-associated macrophages and reducing T regulatory cell (Treg) and chemokine (C-C motif) receptor 2-positive monocyte infiltration in HCC tissue. In these models, VEGFR-2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD-ligand 1 expression in HCC cells was induced in a paracrine manner upon anti-VEGFR-2 blockade in endothelial cells in part through interferon-gamma expression. Moreover, we found that VEGFR-2 blockade increased PD-1 expression in tumor-infiltrating CD4+ cells. We also found that under anti-PD-1 therapy, CD4+ cells promote normalized vessel formation in the face of antiangiogenic therapy with anti-VEGFR-2 antibody.ConclusionsWe show that dual anti-PD-1/VEGFR-2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti-PD-1 therapy-resistant and anti-PD-1 therapy-responsive HCC models.

Dataset Information

Dual Transforming Growth Factor-? and Programmed Death-1 Blockade: A Strategy for Immune-Excluded Tumors?

Publications

Dual Transforming Growth Factor-β and Programmed Death-1 Blockade: A Strategy for Immune-Excluded Tumors?

Similar Datasets

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