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.

Abstract 13287: Dendritic Cells Play a Critical Role in the Initiation of Atherosclerosis

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Mengyao Jin ◽  
Peng Liu
Keyword(s):  
Cell Proliferation ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Critical Role ◽  
Cell Interaction ◽  
Plaque Formation ◽  
T Cell Proliferation ◽  
Control Group

Introduction: Dendritic cells (DCs) that are known as professional antigen-presenting cells have been found to pre-locate in non-inflammatory arterial wall and increasingly accumulate during atherosclerosis progression. Previous findings suggested that residential DCs in the intima are responsible for capturing modified lipids and forming foam cells during the initiation of atherosclerosis. Hypothesis: DC accumulation and enhanced DC-T cell interaction play a critical role in the initiation of atherosclerosis. Methods: We measured plaque formation, vascular DC accumulation and antigen-specific T cell proliferation mediated by isolated aortic cells in ApoE-/- mice, as well as DTR-CD11c/ApoE-/- or DTR-CD11b/ApoE-/- mice for conditional depletion of DCs or macrophages, respectively. A brief high-fat diet for 10 days was used as a model of initial atherosclerosis. Results: In addition to increased intimal DC accumulation and plaque formation in aortic roots, 10 days of HFD induced T cell infiltration in ApoE-/- mice, compared to those without HFD as the control. Isolated aortic cells from mice with 10-day HFD showed stronger capability in inducing antigen-specific T cell proliferation, compare to the control (HFD: 3.14±0.71%; no HFD: 1.56±0.36%; p=0.022). Single diphtheria toxin (DT) injection at day 1 yielded approximately 50% decrease in intimal DC accumulation, as well as 60% attenuation in plaque formation in DTR-CD11c/ApoE-/- mice after 10-day HFD. Capability of stimulating antigen-specific T cell proliferation was also impaired in aortic cells from DC-depleted mice (DT-treated: 1.62±0.30%; PBS-treated: 3.04±0.59%; p= 0.004), along with reduction in indirect conduction of T cell activation. In contrast, no significant changes were found in plaque formation and DC accumulation in DT-injected DTR-CD11b/ApoE-/- mice after 10 days of HFD, compared to control group. Furthermore, depletion of CD11b+ macrophages in either aortas or spleens didn’t alter capability of inducing antigen-specific T cell proliferation in DT-injected mice. Conclusions: These results suggested that vascular DCs rather than macrophages play a more important role in T cell activation and initiation of atherosclerosis.

scholarly journals Involvement of both major histocompatibility complex class II alpha and beta chains in CD4 function indicates a role for ordered oligomerization in T cell activation.

1995 ◽  
Vol 182 (3) ◽  
pp. 779-787 ◽  
Author(s):  
R König ◽  
X Shen ◽  
R N Germain
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Critical Role ◽  
Class Ii ◽  
Specific Receptor ◽  
Single Class ◽  
Histocompatibility Complex ◽  
Beta 2

CD4 is a membrane glycoprotein on T lymphocytes that binds to the same peptide:major histocompatibility complex (MHC) class II molecule recognized by the antigen-specific receptor (TCR), thereby stabilizing interactions between the TCR and peptide;MHC class II complexes and promoting the localization of the src family tyrosine kinase p56lck into the receptor complex. Previous studies identified a solvent-exposed loop on the class II beta 2 domain necessary for binding to CD4 and for eliciting CD4 coreceptor activity. Here, we demonstrate that a second surface-exposed segment of class II is also critical for CD4 function. This site is in the alpha 2 domain, positioned in single class II heterodimers in such a way that it cannot simultaneously interact with the same CD4 molecule as the beta 2 site. The ability of mutations at either site to diminish CD4 function therefore indicates that specifically organized CD4 and/or MHC class II oligomers play a critical role in coreceptor-dependent T cell activation.

scholarly journals PAH- and PCB-induced Alterations of Protein Tyrosine Kinase and Cytokine Gene Transcription in Harbor Seal (Phoca Vitulina) PBMC

2005 ◽  
Vol 12 (2) ◽  
pp. 91-97 ◽  
Author(s):  
Jennifer C. C. Neale ◽  
Thomas P. Kenny ◽  
Ronald S. Tjeerdema ◽  
M. Eric Gershwin
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Tyrosine Kinases ◽  
Cell Activation ◽  
Critical Role ◽  
Harbor Seal ◽  
Lymphocyte Function ◽  
Altered Expression ◽  
Protein Tyrosine

Mechanisms underlyingin vitroimmunomodulatory effects of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) were investigated in harbor seal peripheral leukocytes, via real-time PCR. We examined the relative genetic expression of the protein tyrosine kinases (PTKs)FynandItk, which play a critical role in T cell activation, and IL-2, a cytokine of central importance in initiating adaptive immune responses. IL-1, the macrophage-derived pro-inflammatory cytokine of innate immunity, was also included as a measure of macrophage function. Harbor seal PBMC were exposed to the prototypic immunotoxic PAH benzo[a]pyrene (BaP), 3,3',4,4',5,5'-hexachlorobiphenyl (CB-169), a model immunotoxic PCB, or DMSO (vehicle control). Exposure of Con A-stimulated harbor seal PBMC to both BaP and CB-169 produced significantly altered expression in all four targets relative to vehicle controls. The PTKsFynandItkwere both up-regulated following exposure to BaP and CB-169. In contrast, transcripts for IL-2 and IL-1 were decreased relative to controls by both treatments. Our findings are consistent with those of previous researchers working with human and rodent systems and support a hypothesis of contaminant-altered lymphocyte function mediated (at least in part) by disruption of T cell receptor (TCR) signaling and cytokine production.

scholarly journals Role of Ly-6 in lymphocyte activation. II. Induction of T cell activation by monoclonal anti-Ly-6 antibodies.

1986 ◽  
Vol 164 (3) ◽  
pp. 709-722 ◽  
Author(s):  
T R Malek ◽  
G Ortega ◽  
C Chan ◽  
R A Kroczek ◽  
E M Shevach
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Proliferative Response ◽  
Cell Activation ◽  
Critical Role ◽  
Lymphocyte Activation ◽  
Accessory Cells ◽  
Peripheral T Cells ◽  
Activation Cascade

The Ly-6 locus controls the expression and/or encodes for alloantigenic specificities found primarily on subpopulations of murine T and B lymphocytes. We have recently identified and characterized a new rat mAb, D7, that recognizes a nonpolymorphic Ly-6 specificity. After crosslinking by anti-Ig reagents or by Fc receptor-bearing accessory cells, mAb D7 could induce IL-2 production from T cell hybridomas, and in the presence of PMA could trigger a vigorous proliferative response in resting peripheral T cells. The addition of mAb D7 to cultures of antigen- and alloantigen-, but not mitogen-stimulated T cells resulted in a marked augmentation of the proliferative response. A number of other well-characterized mAbs to Ly-6 locus products could also stimulate a T cell proliferative response after crosslinking by anti-Ig and in the presence of PMA. These results strongly suggest that Ly-6 molecules may play a critical role in the T cell activation cascade, either as receptors for an unidentified soluble or cell-associated ligand or as transducing molecules that modulate signals initiated by antigen stimulation of the T3-Ti complex.

Immunotherapy using activated T cells with chemotherapy for metastatic colorectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 767-767
Author(s):  
Yoichiro Yoshida ◽  
Naoya Aisu ◽  
Hideki Nagano ◽  
Akira Komono ◽  
Daibo Kojima ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Metastatic Colorectal Cancer ◽  
T Cell Activation ◽  
Adoptive Immunotherapy ◽  
Cell Activation ◽  
Critical Role ◽  
Activated T Cells ◽  
Novel Technologies

767 Background: The programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, is demonstrated to induce an immune-mediated response and play a critical role in tumor initiation and development. T cell activation induces effective antitumor immune response in cancer patients. Adoptive immunotherapy of cancer is evolving with the development of novel technologies that generate proliferation of large number of T cells. We evaluated the safety and efficacy of the combination of adoptive immunotherapy using αβ T cells with chemotherapy for metastatic colorectal cancer (mCRC). Methods: Seventeen patients with mCRC received XELOX + bevacizumab + ex vivo expanded αβ T lymphocytes as a first-line chemoimmunotherapy. Results: Median age of the 17 patients (6 men, 11 women) was 64 years (range:38–80). The T cell number was more than 5.0×109 for each infusion. Median progression-free survival was 15.2 months. Response rate was 80% (complete response (CR) = 23.5%, partial response (PR) = 47.1%, stable disease (SD) = 29.4% and progressive disease (PD) = 0%). Most adverse events were mild to moderate in intensity and immunotherapy-associated toxicity was minimal. Conclusions: Combination of adoptive αβ T cell immunotherapy with chemotherapy for mCRC is safe and effective.

Lymphodepletion (LD), tumor-infiltrating lymphocytes (TIL) and high (HD-IL2) versus low-dose (LD-IL2) IL-2 followed by pembrolizumab (pembro) in patients (pts) with metastatic melanoma (MM).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9543-9543
Author(s):  
Rodabe Navroze Amaria ◽  
Cara L. Haymaker ◽  
Marie-Andree Forget ◽  
Roland Bassett ◽  
Janice N. Cormier ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
Adoptive Cell Transfer ◽  
Unknown Primary ◽  
Prior Therapy ◽  
Md Anderson

9543 Background: TIL adoptive cell transfer (ACT) therapy can produce durable responses for MM pts although efficacy appears lower in the era of checkpoint inhibitors. Toxicities from HD-IL2, including sepsis physiology, limits widespread use of this regimen. Suppression of transferred TIL by either tumor cells or the tumor microenvironment could limit TIL responses. Pembro is known to promote T cell activation, thus, we evaluated the efficacy and safety of TIL with pembro with HD-IL2 versus LD-IL2. Methods: Pts with MM who had tumor harvested and cryopreserved TIL at MD Anderson with PS 0-1 and normal organ function were eligible. All pts received a standard LD regimen consisting of cyclophosphamide and fludarabine, followed by infusion of pooled ex-vivo expanded TIL and either HD-IL2 (Arm 1: 720,000 IU/kg IV q 8 hrs up to 15 doses) or LD-IL2 (Arm 2: 2 million IU SC for 14 d). Pts received pembro 200mg IV starting 21 d post T cell infusion every 3 wks for up to 2 yrs. Pts were randomized 1:1 based on stage and LDH. Paired blood and tumor biopsies were obtained prior to LD, prior to first and second dose of pembro and at time of progression. Results: A total of 36 pts were planned to enroll (18 in each arm); however, the protocol met pre-specified futility boundaries in Arm 1 which prompted early closure after treatment of 14 pts (7 in each Arm). Median age was 50 yrs, 6 were female, 8 had cutaneous melanoma, 2 mucosal, 2 uveal and 2 unknown primary. 86% were stage M1c, 14% M1D, 50% had LDH elevation. Median lines of prior therapy were 3 (range 1-6), including prior anti PD-1 in 13 pts. Best overall response was 1 PR (for 10 mos), 2 SD, 3 PD, 1 NE in Arm 1; 1 PR (ongoing over 36 mos), 1 SD, 5 PD in Arm 2. With median follow up of 9.2 mos, PFS was 3.9 mos for Arm 1 and 2.1 mos for Arm 2 (p = 0.99). Median OS was 9.7 mos for Arm 1 and 8.8 mos for Arm 2 (p = 0.71). Toxicity was similar in both Arms but with lower rates of grade 3 febrile neutropenia (57% vs. 71%) and shorter hospital stay (median 16 vs. 18 d) in Arm 2 vs. Arm 1. Conclusions: In a heavily treated pt population, TIL with pembro achieved low response rates. Use of LD-IL2 did not diminish efficacy and may be better tolerated than HD-IL2 for TIL ACT. Correlative studies are ongoing to determine mechanisms of treatment response and failure. Clinical trial information: NCT02500576.

Glycoprotein D, a checkpoint inhibitor of early T-cell activation, to improve immunogenicity and efficacy of an HPV-16 vaccine in preclinical studies.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 71-71
Author(s):  
Hildegund Ertl ◽  
Zhiquan Xiang ◽  
Yan Li ◽  
Andrew Luber ◽  
Colin Magowan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Antigens ◽  
Checkpoint Inhibitor ◽  
Wild Type ◽  
Hpv 16 ◽  
Cell Responses

71 Background: CD8+ T cells can inhibit tumor progression, but their induction is hampered by the low immunogenicity of most tumor antigens. HSV-1 glycoprotein D (gD), when genetically expressed as a fusion protein with tumor antigens, serves as a checkpoint inhibitor of the B and T cell attenuator (BTLA)-herpes virus entry mediator (HVEM) pathway, which acts early during T cell activation. HSV-1 gD thereby augments antigen-driven CD8+ T cell responses. We describe the immunogenicity and efficacy of a chimpanzee adenoviral vector (AdC) vaccine containing a detoxified E7/E6/E5(AdC-gDE765dt) sequence of HPV-16 fused into gD. Methods: The frequency of HPV-16 E7-specific CD8+ T-cells was assessed by tetramer staining in C57/Bl6 mice 14 days after a single IM vaccination with AdC vectors encoding wild-type or mutant HPV-16 oncoproteins expressed within gD, a non-HVEM-binding form of gD or without gD. Efficacy was tested in a TC-1 tumor cell challenge model with mice receiving no treatment or a single IM vaccine injection 3 days after tumor cell transplantation. Mice were followed for 80 days. Results: The addition of gD increases HPV-16 E7-specific CD8+ T-cell frequencies approximately 10-fold. T cell responses are similar to AdC vaccines expressing wild-type or mutant oncoproteins within gD. All AdC-gDE765dt treated mice show delayed tumor progression after a single vaccination with 50% of animals remaining tumor-free at study completion. Conclusions: These results show that the addition of gD, an early checkpoint inhibitor, which acts locally at the site of T cell stimulation, to an HPV-16 vaccine markedly improves the vaccine’s immunogenicity and efficacy. AdC-gDE765dt is currently in GMP manufacture for Phase 1 investigation in HPV-16 infected patients.

scholarly journals Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Min Chen ◽  
Kumar Felix ◽  
Jin Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Types ◽  
Activated T Cells ◽  
Ifn Γ

AbstractAfter stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be determined. Here we show that perforin deficiency in mice, together with the deletion of Fas in DCs (perforin−/−DC-Fas−/−), led to DC accumulation, uncontrolled T-cell activation, and IFN-γ production by CD8+ T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas−/− DCs induced over-activation and IFN-γ production in perforin−/− CD8+ T cells. Neutralization of IFN-γ prevented the spreading of inflammatory responses to different cell types and protected the survival of perforin−/−DC-Fas−/− mice. Our data suggest that perforin and Fas synergize in the maintenance of DC homeostasis to limit T cell activation, and prevent the initiation of an inflammatory cascade.

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