Dendritic Cell-Secreted Cytotoxic T-Lymphocyte-Associated Protein-4 Regulates the T-cell Response by Downmodulating Bystander Surface B7

Halpert, Matthew M.; Konduri, Vanaja; Liang, Dan; Chen, Yun-Yu; Wing, James B.; Paust, Silke; Levitt, Jonathan M.; Decker, William K.

doi:10.1089/scd.2016.0009

Cited by 46 publications

(49 citation statements)

References 50 publications

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“…To our surprise, a low density of CTLA4 þ cells appears to identify a subgroup of CD8 Hi HGSC patients with relatively poor (rather than good) disease outcome as compared with their CD8 Hi CTLA Hi counterparts. Potentially, such an unexpected finding may either reflect the expression of CTLA4 by myeloid cells supporting antitumor immunity (34) or originate from the relatively low number of patients in the CD8 Hi CTLA4 Lo group.…”

Section: Discussionmentioning

confidence: 99%

TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer

Fučíková

Rakova

Hensler

et al. 2019

Clinical Cancer Research

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Purpose: In multiple oncological settings, expression of the coinhibitory ligand PD-L1 by malignant cells and tumor infiltration by immune cells expressing coinhibitory receptors such as PD-1, CTLA4, LAG-3, or TIM-3 conveys prognostic or predictive information. Conversely, the impact of these features of the tumor microenvironment on disease outcome among high-grade serous carcinoma (HGSC) patients remains controversial. Experimental Design: We harnessed a retrospective cohort of 80 chemotherapy-na€ ve HGSC patients to investigate PD-L1 expression and tumor infiltration by CD8 þ T cells, CD20 þ B cells, DC-LAMP þ dendritic cells as well as by PD-1 þ , CTLA4 þ , LAG-3 þ , and TIM-3 þ cells in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on a second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 308 HGSC samples was used as a confirmatory approach. Results: High levels of PD-L1 and high densities of PD-1 þ cells in the microenvironment of HGSCs were strongly associated with an immune contexture characterized by a robust T H 1 polarization and cytotoxic orientation that enabled superior clinical benefits. Moreover, PD-1 þ TIM-3 þ CD8 þ T cells presented all features of functional exhaustion and correlated with poor disease outcome. However, although PD-L1 levels and tumor infiltration by TIM-3 þ cells improved patient stratification based on the intratumoral abundance of CD8 þ T cells, the amount of PD-1 þ cells failed to do so. Conclusions: Our data indicate that PD-L1 and TIM-3 constitute prognostically relevant biomarkers of active and suppressed immune responses against HGSC, respectively.

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Section: Discussionmentioning

confidence: 99%

TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer

Fučíková

Rakova

Hensler

et al. 2019

Clinical Cancer Research

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“…Although initially identified as a T cell-specific protein, CTLA-4 is now known to also be expressed in B cells and dendritic cells (DC) [34,35]. CTLA-4 inhibits T cell responses by several means.…”

Section: Introductionmentioning

confidence: 99%

CTLA-4 Mediates Inhibitory Function of Mesenchymal Stem/Stromal Cells

Gaber

Schönbeck

Hoff

et al. 2018

IJMS

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Mesenchymal stem/stromal cells (MSCs) are stem cells of the connective tissue, possess a plastic phenotype, and are able to differentiate into various tissues. Besides their role in tissue regeneration, MSCs perform additional functions as a modulator or inhibitor of immune responses. Due to their pleiotropic function, MSCs have also gained therapeutic importance for the treatment of autoimmune diseases and for improving fracture healing and cartilage regeneration. However, the therapeutic/immunomodulatory mode of action of MSCs is largely unknown. Here, we describe that MSCs express the inhibitory receptor CTLA-4 (cytotoxic T lymphocyte antigen 4). We show that depending on the environmental conditions, MSCs express different isoforms of CTLA-4 with the secreted isoform (sCTLA-4) being the most abundant under hypoxic conditions. Furthermore, we demonstrate that the immunosuppressive function of MSCs is mediated mainly by the secretion of CTLA-4. These findings open new ways for treatment when tissue regeneration/fracture healing is difficult.

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“…We have previously demonstrated that the loading of DC with antigenically similar (homologous) MHC class I and II antigens leads to a cell-intrinsic upregulation of T H 1 polarization. This polarization consists of a differential ability to secrete IL-12, IL-23, CTLA-4, 11 and the novel T H 1 polarizing cytokine AIMp1, [12][13][14][15] to upregulate surface CD83 and CD40, and to induce the preferential generation of IFNg-secreting CD8 C cytolytic T-cells. DC loaded in this manner also demonstrate a substantial reorganization of the transcriptome, exhibiting a transcriptional profile significantly different from alternatively loaded DC by over 1,700 transcripts in areas such as interferon signaling, antigen-presentation, antiviral responses, protein ubiquitination, and DC licensing.…”

Section: Introductionmentioning

confidence: 99%

Chemo-immunotherapy mediates durable cure of orthotopic Kras^G12D/p53^−/−pancreatic ductal adenocarcinoma

Konduri

Halpert

et al. 2016

OncoImmunology

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Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, exhibiting a five-year overall survival (OS) of only 7% despite aggressive standard of care. Recent advances in immunotherapy suggest potential application of immune-based treatment approaches to PDAC. To explore this concept further, we treated orthotopically established K-ras G12D /p53¡/¡ PDAC tumors with gemcitabine and a cell-based vaccine previously shown to generate durable cell-mediated (T H 1) immunity. Tumor progression was monitored by IVIS. The results indicated that the combination of chemotherapy and dendritic cell (DC) vaccination was effective in eliminating tumor, preventing metastasis and recurrence, and significantly enhancing OS. No animal that received the combination therapy relapsed, while mice that received gemcitabine-only or vaccine-only regimens relapsed and progressed. Analysis of circulating PBMC demonstrated that mice receiving the combination therapy exhibited significantly elevated levels of CD8 C

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Dendritic Cell-Secreted Cytotoxic T-Lymphocyte-Associated Protein-4 Regulates the T-cell Response by Downmodulating Bystander Surface B7

Cited by 46 publications

References 50 publications

TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer

TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer

CTLA-4 Mediates Inhibitory Function of Mesenchymal Stem/Stromal Cells

Chemo-immunotherapy mediates durable cure of orthotopic Kras^G12D/p53^−/−pancreatic ductal adenocarcinoma

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Dendritic Cell-Secreted Cytotoxic T-Lymphocyte-Associated Protein-4 Regulates the T-cell Response by Downmodulating Bystander Surface B7

Cited by 46 publications

References 50 publications

TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer

TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer

CTLA-4 Mediates Inhibitory Function of Mesenchymal Stem/Stromal Cells

Chemo-immunotherapy mediates durable cure of orthotopic KrasG12D/p53−/−pancreatic ductal adenocarcinoma

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Chemo-immunotherapy mediates durable cure of orthotopic Kras^G12D/p53^−/−pancreatic ductal adenocarcinoma