Blockade of B7-H1 improves myeloid dendritic cell–mediated antitumor immunity

Curiel, Tyler J.; Wei, Shuang; Dong, Haidong; Álvarez, Xavier; Cheng, Pui; Mottram, Peter; Krzysiek, Roman; Knutson, Keith L.; Daniel, Ben; Zimmermann, Maria; David, Odile; Burow, Matthew E.; Gordon, Alan N.; Dhurandhar, Nina; Myers, Leann; Berggren, Ruth E.; Hemminki, Akseli; Alvarez, Ronald D.; Émilie, Dominique; Curiel, David T.; Chen, Lieping; Zou, Weiping

doi:10.1038/nm863

Cited by 1,135 publications

(948 citation statements)

References 31 publications

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“…30 , 31 Therefore, we next investigated the effect of dual PD-1 and TIGIT blockade on the myeloid compartment of brain TILs. Mice in the control arm were found to have significantly higher infiltration of DCs (CD11b + CD11 c + cells) compared to the combination arm ( p = 0.0169), whereas neither anti-PD-1 nor anti-TIGIT alone exerted a similar effect relative to control (Fig.…”

Section: Resultsmentioning

confidence: 99%

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

et al. 2018

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The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

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Section: Resultsmentioning

confidence: 99%

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

et al. 2018

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“…The expression of HLA-DR and of the costimulatory molecules OX40L and, to a lesser extent, ICOS-L was also enhanced in PG/DC. Interaction of these molecules with their counter-receptors present on T cells are important for both the development of regulatory T (ICOS-L, B7-H1) [30,37] or Th2 cells (ICOS-L and OX40L) [38,39] and for the control of effector T cells. Although Ag capture and expression of MHC class II were increased, PG/DC have a lower ability to activate naive T cells under conditions where Ag processing is required.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin D₂ affects the differentiation and functions of human dendritic cells: impact on the T cell response

et al. 2005

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The local environment in which dendritic cells (DC) differentiate is important for the acquisition of their immunostimulatory properties. Since prostaglandin D 2 (PGD 2 ), a major prostanoid produced during inflammatory reactions, is involved in the control of immune responses, its effect on the differentiation and functions of human monocytederived dendritic cells (MDDC) was studied. We show that DC differentiated in the presence of PGD 2 (PG/DC) have an unusual phenotype, with modifications in the expression of molecules involved in antigen (Ag) capture and presentation, leading to higher endocytic and Ag-processing activities. However, under conditions that necessitated Ag processing and presentation, PG/DC have an impaired ability to stimulate naive T cells, whereas superAg-pulsed DC efficiently promote their proliferation. Upon lipopolysaccharide or TNF-a/IL-1b stimulation, PG/DC phenotypically mature but produce abnormal amounts of immunoregulatory cytokines (decreased IL-12p70/IL-10 ratio). Moreover, mature PG/DC fail to up-regulate the chemokine receptor CCR7 and show an impaired migration towards its ligand CCL19. Finally, PG/DC favor the differentiation of naive T cells toward Th2 cells, an effect dependent on IL-10 and inducible costimulator ligand expression by DC. Most of the herein described effects of PGD 2 on MDDC can be reproduced, usually with a higher efficacy, with a selective D prostanoid receptor (DP)1, but not DP2, agonist. Taken as a whole, these results demonstrate that PGD 2 impacts DC differentiation and functions, and extend the concept that it exerts important roles in immunity.

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“…Most myeloid DCs found in human ovarian, breast, prostate and renal cell carcinoma are therefore immature and may induce tumor immunotolerance [231][232][233][234]. Tumor-secreted IL-10 and VEGF also induce expression of B7-H1 on myeloid dendritic cells, a ligand for PD-1 receptor expressed on suppressor T cells [238]. A study published this year demonstrates that the metastatic ability of melanoma and colon cancer cells expressing B7-H1 is abolished in PD-1-deficient mice and that tumors also grow more slowly [239].…”

Section: Nks and Dcsmentioning

confidence: 99%

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

Kopfstein

Christofori

2006

Cell. Mol. Life Sci.

207

160

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Abstract. The fatality of cancer predominantly results from the dissemination of primary tumor cells to distant sites and the subsequent formation of metastases. During tumor progression, some of the primary tumor cells as well as the tumor microenvironment undergo characteristic molecular changes, which are essential for the metastatic dissemination of tumor cells. In this review, we will discuss recent insights into pro-metastatic events occurring in tumor cells themselves and in the tumor stroma. Tumor cell-intrinsic alterations include the loss of cell polarity and alterations in cell-cell and cell-matrix Cell. Mol. Life Sci. 63 (2006) 449-468 1420-682X/06/040449-20 DOI 10.1007/s00018-005-5296-8 © Birkhäuser Verlag, Basel, 2006 adhesion as well as deregulated receptor kinase signaling, which together support detachment, migration and invasion of tumor cells. On the other hand, the tumor stroma, including endothelial cells, fibroblasts and cells of the immune system, is engaged in an active molecular crosstalk within the tumor microenvironment. Subsequent activation of blood vessel and lymph vessel angiogenesis together with inflammatory and immune-suppressive responses further promotes cancer cell migration and invasion, as well as initiation of the metastatic process.

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Blockade of B7-H1 improves myeloid dendritic cell–mediated antitumor immunity

Cited by 1,135 publications

References 31 publications

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

Prostaglandin D₂ affects the differentiation and functions of human dendritic cells: impact on the T cell response

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

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Blockade of B7-H1 improves myeloid dendritic cell–mediated antitumor immunity

Cited by 1,135 publications

References 31 publications

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

Prostaglandin D2 affects the differentiation and functions of human dendritic cells: impact on the T cell response

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

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Prostaglandin D₂ affects the differentiation and functions of human dendritic cells: impact on the T cell response