scholarly journals Targeting Cross-Presentation as a Route to Improve the Efficiency of Peptide-Based Cancer Vaccines

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6189
Author(s):  
Ben Wylie ◽  
Ferrer Ong ◽  
Hanane Belhoul-Fakir ◽  
Kristin Priebatsch ◽  
Heique Bogdawa ◽  
...  
Keyword(s):  
Tumor Immunity ◽  
Critical Role ◽  
Peptide Vaccine ◽  
Vaccination Strategy ◽  
Endosomal Escape ◽  
Antigen Delivery ◽  
Cross Presentation ◽  
Murine Melanoma ◽  
Presentation Pathway ◽  
Melanoma Model

Cross-presenting dendritic cells (DC) offer an attractive target for vaccination due to their unique ability to process exogenous antigens for presentation on MHC class I molecules. Recent reports have established that these DC express unique surface receptors and play a critical role in the initiation of anti-tumor immunity, opening the way for the development of vaccination strategies specifically targeting these cells. This study investigated whether targeting cross-presenting DC by two complementary mechanisms could improve vaccine effectiveness, in both a viral setting and in a murine melanoma model. Our novel vaccine construct contained the XCL1 ligand, to target uptake to XCR1+ cross-presenting DC, and a cell penetrating peptide (CPP) with endosomal escape properties, to enhance antigen delivery into the cross-presentation pathway. Using a prime-boost regimen, we demonstrated robust expansion of antigen-specific T cells following vaccination with our CPP-linked peptide vaccine and protective immunity against HSV-1 skin infection, where vaccine epitopes were natively expressed by the virus. Additionally, our novel vaccination strategy slowed tumor outgrowth in a B16 murine melanoma model, compared to adjuvant only controls, suggesting antigen-specific anti-tumor immunity was generated following vaccination. These findings suggest that novel strategies to target the antigen cross-presentation pathway in DC may be beneficial for the generation of anti-tumor immunity.

Abstract 4055: Immune checkpoint DNA vaccines enhance anti-tumor immunity in murine melanoma model

2020 ◽  
Author(s):  
Keng-Hsueh Lan ◽  
Raghava Sriramaneni ◽  
Justin C. Jagodinsky ◽  
Claire Baniel ◽  
Amy Erbe-Gurel ◽  
...  
Keyword(s):  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Dna Vaccines ◽  
Murine Melanoma ◽  
Melanoma Model

Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2465-2472 ◽  
Author(s):  
Max Schnurr ◽  
Qiyuan Chen ◽  
Amanda Shin ◽  
Weisan Chen ◽  
Tracey Toy ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Complexes ◽  
Tumor Antigen ◽  
Antigen Processing ◽  
Antigen Delivery ◽  
Cross Presentation ◽  
Mhc Ii ◽  
Presentation Pathway ◽  
Broad Array

AbstractDendritic cells (DCs) are being evaluated for cancer immunotherapy due to their unique ability to induce tumor-directed T-cell responses. Here we report that the type of human DC, the mode of activation, and the strategy for delivery of antigen are 3 critical factors for efficient stimulation of tumor-specific CD8+ and CD4+ T cells. Only CD1c+ blood DCs and monocyte-derived DCs (MoDCs) were capable of presenting epitopes of the full-length tumor antigen NY-ESO-1 on both major histocompatibility complex (MHC) class I (cross-presentation) and MHC II, whereas plasmacytoid DCs were limited to MHC II presentation. Cross-presentation was inefficient for soluble protein, but highly efficient for antigen-antibody immune complexes (NY-ESO-1/IC) and for protein formulated with ISCOMATRIX adjuvant (NY-ESO-1/IMX). DC activation with CD40L further enhanced cross-presentation efficiency. The mode of antigen delivery was found to be a determining factor for cytosolic proteolysis by DCs. Immune complexes (ICs) targeted a slow, proteasome-dependent cross-presentation pathway, whereas ISCOMATRIX (IMX) targeted a fast, proteasome-independent pathway. Both cross-presentation pathways resulted in a long-lived, T-cell stimulatory capacity, which was maintained for several days longer than for DCs pulsed with peptide. This may provide DCs with ample opportunities for sensitizing tumor-specific T cells against a broad array of tumor antigen epitopes in lymph nodes.

scholarly journals The Potential of T Cell Factor 1 in Sustaining CD8+ T Lymphocyte-Directed Anti-Tumor Immunity

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 515
Author(s):  
Sungmin Jung ◽  
Jea-Hyun Baek
Keyword(s):  
T Cell ◽  
Tumor Immunity ◽  
T Lymphocyte ◽  
Critical Role ◽  
Cd8 T Cell ◽  
Immune Checkpoint Blockade ◽  
Viral Escape ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
T Cell Factor

T cell factor 1 (TCF1) is a transcription factor that has been highlighted to play a critical role in the promotion of T cell proliferation and maintenance of cell stemness in the embryonic and CD8+ T cell populations. The regulatory nature of TCF1 in CD8+ T cells is of great significance, especially within the context of T cell exhaustion, which is linked to the tumor and viral escape in pathological contexts. Indeed, inhibitory signals, such as programmed cell death 1 (PD-1) and cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), expressed on exhausted T lymphocytes (TEX), have become major therapeutic targets in immune checkpoint blockade (ICB) therapy. The significance of TCF1 in the sustenance of CTL-mediated immunity against pathogens and tumors, as well as its recently observed necessity for an effective anti-tumor immune response in ICB therapy, presents TCF1 as a potentially significant biomarker and/or therapeutic target for overcoming CD8+ T cell exhaustion and resistance to ICB therapy. In this review, we aim to outline the recent findings on the role of TCF1 in T cell development and discuss its implications in anti-tumor immunity.

scholarly journals Dendritic Cell Tumor Vaccination via Fc Gamma Receptor Targeting: Lessons Learned from Pre-Clinical and Translational Studies

Vaccines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 409
Author(s):  
Enrique Gómez Alcaide ◽  
Sinduya Krishnarajah ◽  
Fabian Junker
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
Lessons Learned ◽  
Antigen Delivery ◽  
Tumor Vaccination ◽  
Translational Studies

Despite significant recent improvements in the field of immunotherapy, cancer remains a heavy burden on patients and healthcare systems. In recent years, immunotherapies have led to remarkable strides in treating certain cancers. However, despite the success of checkpoint inhibitors and the advent of cellular therapies, novel strategies need to be explored to (1) improve treatment in patients where these approaches fail and (2) make such treatments widely and financially accessible. Vaccines based on tumor antigens (Ag) have emerged as an innovative strategy with the potential to address these areas. Here, we review the fundamental aspects relevant for the development of cancer vaccines and the critical role of dendritic cells (DCs) in this process. We first offer a general overview of DC biology and routes of Ag presentation eliciting effective T cell-mediated immune responses. We then present new therapeutic avenues specifically targeting Fc gamma receptors (FcγR) as a means to deliver antigen selectively to DCs and its effects on T-cell activation. We present an overview of the mechanistic aspects of FcγR-mediated DC targeting, as well as potential tumor vaccination strategies based on preclinical and translational studies. In particular, we highlight recent developments in the field of recombinant immune complex-like large molecules and their potential for DC-mediated tumor vaccination in the clinic. These findings go beyond cancer research and may be of relevance for other disease areas that could benefit from FcγR-targeted antigen delivery, such as autoimmunity and infectious diseases.

Proline prodrug of melphalan, prophalan-l, demonstrates high therapeutic index in a murine melanoma model

2007 ◽  
Vol 67 (3) ◽  
pp. 752-758 ◽  
Author(s):  
Sachin Mittal ◽  
Yasuhiro Tsume ◽  
Christopher P. Landowski ◽  
Kyung-Dall Lee ◽  
John M. Hilfinger ◽  
...  
Keyword(s):  
Therapeutic Index ◽  
Murine Melanoma ◽  
Melanoma Model ◽  
High Therapeutic Index

scholarly journals Photothermal Therapy Using Gold Nanorods and Near-Infrared Light in a Murine Melanoma Model Increases Survival and Decreases Tumor Volume

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Mary K. Popp ◽  
Imane Oubou ◽  
Colin Shepherd ◽  
Zachary Nager ◽  
Courtney Anderson ◽  
...  
Keyword(s):  
Light Source ◽  
Gold Nanorods ◽  
Photothermal Therapy ◽  
Near Infrared ◽  
Tumor Volume ◽  
Infrared Light ◽  
Led Light ◽  
Murine Melanoma ◽  
Nir Light ◽  
Melanoma Model

Photothermal therapy (PTT) treatments have shown strong potential in treating tumors through their ability to target destructive heat preferentially to tumor regions. In this paper we demonstrate that PTT in a murine melanoma model using gold nanorods (GNRs) and near-infrared (NIR) light decreases tumor volume and increases animal survival to an extent that is comparable to the current generation of melanoma drugs. GNRs, in particular, have shown a strong ability to reach ablative temperatures quickly in tumors when exposed to NIR light. The current research tests the efficacy of GNRs PTT in a difficult and fast growing murine melanoma model using a NIR light-emitting diode (LED) light source. LED light sources in the NIR spectrum could provide a safer and more practical approach to photothermal therapy than lasers. We also show that the LED light source can effectively and quickly heatin vitroandin vivomodels to ablative temperatures when combined with GNRs. We anticipate that this approach could have significant implications for human cancer therapy.

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