Faculty Opinions recommendation of WDFY4 is required for cross-presentation in response to viral and tumor antigens.

2019 ◽  
Author(s):  
Malini Raghavan ◽  
Jie Geng
Keyword(s):  
Tumor Antigens ◽  
Cross Presentation

scholarly journals WDFY4 is required for cross-presentation in response to viral and tumor antigens

Science ◽  
2018 ◽  
Vol 362 (6415) ◽  
pp. 694-699 ◽  
Author(s):  
Derek J. Theisen ◽  
Jesse T. Davidson ◽  
Carlos G. Briseño ◽  
Marco Gargaro ◽  
Elvin J. Lauron ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tumor Antigens ◽  
Critical Role ◽  
Tumor Rejection ◽  
Interleukin 12 ◽  
Cross Presentation ◽  
Histocompatibility Complex ◽  
Crispr Screen

During the process of cross-presentation, viral or tumor-derived antigens are presented to CD8+ T cells by Batf3-dependent CD8α+/XCR1+ classical dendritic cells (cDC1s). We designed a functional CRISPR screen for previously unknown regulators of cross-presentation, and identified the BEACH domain–containing protein WDFY4 as essential for cross-presentation of cell-associated antigens by cDC1s in mice. However, WDFY4 was not required for major histocompatibility complex class II presentation, nor for cross-presentation by monocyte-derived dendritic cells. In contrast to Batf3–/– mice, Wdfy4–/– mice displayed normal lymphoid and nonlymphoid cDC1 populations that produce interleukin-12 and protect against Toxoplasma gondii infection. However, similar to Batf3–/– mice, Wdfy4–/– mice failed to prime virus-specific CD8+ T cells in vivo or induce tumor rejection, revealing a critical role for cross-presentation in antiviral and antitumor immunity.

scholarly journals Selective tumor antigen vaccine delivery to human CD169+antigen-presenting cells using ganglioside-liposomes

2020 ◽  
Vol 117 (44) ◽  
pp. 27528-27539
Author(s):  
Alsya J. Affandi ◽  
Joanna Grabowska ◽  
Katarzyna Olesek ◽  
Miguel Lopez Venegas ◽  
Arnaud Barbaria ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Antigen ◽  
Tumor Antigens ◽  
Ex Vivo ◽  
Antigen Presenting Cells ◽  
Dependent Manner ◽  
Cross Presentation ◽  
Vaccine Carrier ◽  
Antigen Presenting

Priming of CD8+T cells by dendritic cells (DCs) is crucial for the generation of effective antitumor immune responses. Here, we describe a liposomal vaccine carrier that delivers tumor antigens to human CD169/Siglec-1+antigen-presenting cells using gangliosides as targeting ligands. Ganglioside-liposomes specifically bound to CD169 and were internalized by in vitro-generated monocyte-derived DCs (moDCs) and macrophages and by ex vivo-isolated splenic macrophages in a CD169-dependent manner. In blood, high-dimensional reduction analysis revealed that ganglioside-liposomes specifically targeted CD14+CD169+monocytes and Axl+CD169+DCs. Liposomal codelivery of tumor antigen and Toll-like receptor ligand to CD169+moDCs and Axl+CD169+DCs led to cytokine production and robust cross-presentation and activation of tumor antigen-specific CD8+T cells. Finally, Axl+CD169+DCs were present in cancer patients and efficiently captured ganglioside-liposomes. Our findings demonstrate a nanovaccine platform targeting CD169+DCs to drive antitumor T cell responses.

scholarly journals Increased expression of HSP70 by colon cancer cells is not always associated with access to the dendritic cell cross-presentation pathway

2007 ◽  
Vol 12 (2) ◽  
Author(s):  
Lina Matera ◽  
Sarah Forno ◽  
Alessandra Galetto ◽  
Francesco Moro ◽  
Stefano Garetto ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Tumor Antigens ◽  
Normal Mucosa ◽  
Carcinoma Cells ◽  
Specific Marker ◽  
Cytotoxic Lymphocyte ◽  
Specific Expression ◽  
Ctl Response ◽  
Cross Presentation ◽  
Presentation Pathway

AbstractDendritic cells (DCs) are highly specialized antigen-presenting cells endowed with the unique ability to not only present exogenous antigens upon exposure to MHC II, but also to cross-present these upon exposure to MHC I. This property was exploited to generate the tumor-specific CD8 cytotoxic lymphocyte (CTL) response in DCs-based cancer vaccine protocols. In this context, the source of tumor antigens remains a critical challenge. A crude tumor in the context of danger signals is believed to represent an efficient source of tumor antigens (TAs) for DCs loading. In our previous work, increased DCs cross-presentation of antigens from necrotic gastric carcinoma cells paralleled up-regulation of the heat shock protein hsp70. We studied the expression of hsp70 on primary colon carcinoma cells and its relevance in the cross-priming of anti-tumor CTL by tumor-loaded DCs. Hsp70 was expressed on all three of the tumors studied, but was never detected in the peritumoral normal mucosa (NM). The uptake of the tumor induced a trend towards down-modulation of the monocyte-specific marker CD14, but had no effect on the chemokine receptors CCR4 and CCR7. The IFN-γ enzyme-linked immunospot assay (ELIspot) showed cross-priming of CTL by tumor-loaded but not NM-loaded DCs in four of the six cases studied. The CTL response generated in DC+tumor cultures was directed towards the tumor, but not towards NM, and it was characterized by refractoriness to polyclonal (Ca ionophores, PKC activators) stimuli. Of the three CTL-generating tumors, only one expressed hsp70. This data indicates a tumor-specific expression of hsp70, but does not support its relevance in the DC cross-presentation of TAs.

Abstract B051: Super cross-presentation of tumor antigens by synthetic design of an anti-phosphatidylserine bridge protein

2016 ◽  
Author(s):  
Daniel Corey ◽  
Aaron Ring ◽  
Melissa McCracken ◽  
Masanori Miyanishi ◽  
Sydney Gordon ◽  
...  
Keyword(s):  
Tumor Antigens ◽  
Cross Presentation

Processing and cross-presentation of individual HLA-A, -B, or -C epitopes from NY-ESO-1 or an HLA-A epitope for Melan-A differ according to the mode of antigen delivery

Blood ◽  
2010 ◽  
Vol 116 (2) ◽  
pp. 218-225 ◽  
Author(s):  
Neil C. Robson ◽  
Tristan McAlpine ◽  
Ashley J. Knights ◽  
Max Schnurr ◽  
Amanda Shin ◽  
...  
Keyword(s):  
Tumor Antigens ◽  
Human Leukocyte ◽  
Full Length ◽  
Antigen Delivery ◽  
Cross Presentation ◽  
Endosomal Acidification ◽  
Therapeutic Cancer Vaccines ◽  
First Time ◽  
Cancer Testis

Abstract The ability of dendritic cells (DCs) to cross-present protein tumor antigens to cytotoxic T lymphocytes (CTLs) underpins the success of therapeutic cancer vaccines. We studied cross-presentation of the cancer/testis antigen, NY-ESO-1, and the melanoma differentiation antigen, Melan-A by human DC subsets. Monocyte-derived DCs (MoDCs) efficiently cross-presented human leukocyte associated (HLA)–A2-restricted epitopes from either a formulated NY-ESO-1/ISCOMATRIX vaccine or when either antigen was mixed with ISCOMATRIX adjuvant. HLA-A2 epitope generation required endosomal acidification and was proteasome-independent for NY-ESO-1 and proteasome-dependent for Melan-A. Both MoDCs and CD1c+ blood DCs cross-presented NY-ESO-1–specific HLA-A2157-165–, HLA-B760-72–, and HLA-Cw392-100–restricted epitopes when formulated as an NY-ESO-1/ISCOMATRIX vaccine, but this was limited when NY-ESO-1 and ISCOMATRIX adjuvant were added separately to the DC cultures. Finally, cross-presentation of NY-ESO-1157-165/HLA-A2, NY-ESO-160-72/HLA-B7, and NY-ESO-192-100/HLA-Cw3 epitopes was proteasome-dependent when formulated as immune complexes (ICs) but only proteasome-dependent for NY-ESO-160-72/HLA-B7–restricted cross-presentation facilitated by ISCOMATRIX adjuvant. We demonstrate, for the first time, proteasome-dependent and independent cross-presentation of HLA-A–, B–, and C–restricted epitopes within the same full-length tumor antigen by human DCs. Our findings identify important differences in the capacities of human DC subsets to cross-present clinically relevant, full-length tumor antigens and how vaccine formulation impacts CTL responses in vivo.

scholarly journals P02.02 Generating neo- and self-antigen screening libraries for class II HLA presentation

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A20.2-A20
Author(s):  
V Pinamonti ◽  
N Felix ◽  
JM Lindner
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Tumor Antigens ◽  
Cell Receptor ◽  
Class Ii ◽  
Patient Specific ◽  
Spectrometric Analysis ◽  
Cross Presentation ◽  
Class Ii Mhc ◽  
Antigen Presenting

BackgroundThe identification of neo-antigens presented by tumor cells is an essential tool for cancer prevention, diagnosis, and therapy. Current approaches frequently involve mass spectrometric analysis, but these workflows do not concomitantly identify the cognate T-cell receptor. Likewise, TCR functional screens are often limited to a subset of predicted neo-epitopes.Materials and MethodsHere, we present a new method for the generation of an un-biased antigen-presenting library. Due to the genomic instability of tumors, patient-specific libraries will be cloned using random primers, ensuring the cloning of tumor-specific transcribed regions. This approach will not only address class I presentation of intracellular tumor antigens, but is also designed to simultaneously screen for cross-presentation on class II MHC complexes by professional antigen-presenting cells, an increasingly important component of anti-tumor immune responses. To guarantee presentation of genetically encoded antigens on class II MHC complexes, a signal motif for chaperone-mediated autophagy (CMA) is introduced in front of the cDNA sequence. Furthermore, antigens will be processed by the intracellular machinery, avoiding potential restrictions on spliced peptides.ConclusionsOnce established, these libraries can be exploited in high-throughput screens to functionally identify neo-antigens together with their corresponding T-cell receptor.Disclosure InformationV. Pinamonti: Other; Significant; Janssen. N. Felix: Other; Significant; Janssen. J.M. Lindner: Other; Significant; Janssen.

scholarly journals TIM4 expression by dendritic cells mediates uptake of tumor-associated antigens and anti-tumor responses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nicoletta Caronni ◽  
Giulia Maria Piperno ◽  
Francesca Simoncello ◽  
Oriana Romano ◽  
Simone Vodret ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tumor Antigens ◽  
Immune Surveillance ◽  
Normal Lung ◽  
Mouse Lung ◽  
Cross Presentation ◽  
Phosphatidylserine Receptor ◽  
Lung Adenocarcinomas

AbstractAcquisition of cell-associated tumor antigens by type 1 dendritic cells (cDC1) is essential to induce and sustain tumor specific CD8+ T cells via cross-presentation. Here we show that capture and engulfment of cell associated antigens by tissue resident lung cDC1 is inhibited during progression of mouse lung tumors. Mechanistically, loss of phagocytosis is linked to tumor-mediated downregulation of the phosphatidylserine receptor TIM4, that is highly expressed in normal lung resident cDC1. TIM4 receptor blockade and conditional cDC1 deletion impair activation of tumor specific CD8+ T cells and promote tumor progression. In human lung adenocarcinomas, TIM4 transcripts increase the prognostic value of a cDC1 signature and predict responses to PD-1 treatment. Thus, TIM4 on lung resident cDC1 contributes to immune surveillance and its expression is suppressed in advanced tumors.

scholarly journals NADPH oxidase controls phagosomal pH and antigen cross-presentation in human dendritic cells

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4712-4722 ◽  
Author(s):  
Adriana R. Mantegazza ◽  
Ariel Savina ◽  
Mónica Vermeulen ◽  
Laura Pérez ◽  
Jorge Geffner ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nadph Oxidase ◽  
Tumor Antigens ◽  
Phagocytic Cells ◽  
Cross Presentation ◽  
Phagocyte Nadph Oxidase ◽  
Healthy Donors ◽  
Endosomal Ph ◽  
Human Dendritic Cells ◽  
Model Tumor

Abstract The phagocyte NADPH oxidase (NOX2) is critical for the bactericidal activity of phagocytic cells and plays a major role in innate immunity. We showed recently that NOX2 activity in mouse dendritic cells (DCs) prevents acidification of phagosomes, promoting antigen cross-presentation. Inorder to investigate the role of NOX2 in the regulation of the phagosomal pH in human DCs, we analyzed the production of reactive oxygen species (ROS) and the phagosomal/endosomal pH in monocyte-derived DCs and macrophages (MØs) from healthy donors or patients with chronic granulomatous disease (CGD). As expected, we found that human MØs acidify their phagosomes more efficiently than human DCs. Accordingly, the expression of the vacuolar proton ATPase (V-H+-ATPase) was higher in MØs than in DCs. Phagosomal ROS production, however, was also higher in MØs than in DCs, due to higher levels of gp91phox expression and recruitment to phagosomes. In contrast, in the absence of active NOX2, the phagosomal and endosomal pH decreased. Both in the presence of a NOX2 inhibitor and in DCs derived from patients with CGD, the cross-presentation of 2 model tumor antigens was impaired. We conclude that NOX2 activity participates in the regulation of the phagosomal and endosomal pH in human DCs, and is required for efficient antigen cross-presentation.

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