scholarly journals Agonistic CD40 Antibodies in Cancer Treatment

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1302
Author(s):  
Dijana Djureinovic ◽  
Meina Wang ◽  
Harriet M. Kluger
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Clinical Development ◽  
The Cancer Genome Atlas ◽  
Early Phase Clinical Trials ◽  
Antigen Presenting

CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased antigen presentation, maturation (licensing) of dendritic cells, and activation of CD8+ T cells. Here we analyzed gene expression data from The Cancer Genome Atlas in melanoma, renal cell carcinoma, and pancreatic adenocarcinoma and found correlations between CD40 and several genes involved in antigen presentation and T cell function, supporting further exploration of CD40 agonists to treat cancer. Agonist CD40 antibodies have induced anti-tumor effects in several tumor models and the effect has been more pronounced when used in combination with other treatments (immune checkpoint inhibition, chemotherapy, and colony-stimulating factor 1 receptor inhibition). The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies.

IκB kinase 2 but not NF-κB–inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 983-991 ◽  
Author(s):  
Evangelos Andreakos ◽  
Clive Smith ◽  
Claudia Monaco ◽  
Fionula M. Brennan ◽  
Brian M. Foxwell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mixed Lymphocyte Reaction ◽  
Dominant Negative ◽  
Allogeneic Mixed Lymphocyte Reaction ◽  
Iκb Kinase ◽  
Antigen Presenting

AbstractAlthough dendritic cells (DCs) are the most potent antigen-presenting cells involved in numerous physiologic and pathologic processes, little is known about the signaling pathways that regulate DC activation and antigen-presenting function. Recently, we demonstrated that nuclear factor (NF)-κB activation is central to that process, as overexpression of IκBα blocks the allogeneic mixed lymphocyte reaction (MLR), an in vitro model of T-cell activation. In this study, we investigated the role of 2 putative NF-κB–inducing components, NF-κB–inducing kinase (NIK), and IκB kinase 2 (IKK2). Using an adenoviral gene transfer method to efficiently express dominant-negative (dn) forms of these molecules in monocyte-derived DCs, we found that IKK2dn but not NIKdn inhibited the allogeneic MLR. When DCs were fixed, this inhibitory effect of IKK2dn was lost, suggesting that IKK2 is involved in T-cell–derived signals that enhance DC antigen presentation during the allogeneic MLR period and does not have an effect on viability or differentiation state of DCs prior to coculture with T cells. One such signal is likely to be CD40 ligand (CD40L), as IKK2dn blocked CD40L but not lipopolysaccharide (LPS)–induced NF-κB activation, cytokine production, and up-regulation of costimulatory molecules and HLA-DR in DCs. In summary, our results demonstrate that IKK2 is essential for DC activation induced by CD40L or contact with allogeneic T cells, but not by LPS, whereas NIK is not required for any of these signals. In addition, our results support IKK2 as a potential therapeutic target for the down-regulation of unwanted immune responses that may occur during transplantation or autoimmunity.

scholarly journals Cancer immune therapy with PD-1-dependent CD137 co-stimulation provides localized tumour killing without systemic toxicity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yunqian Qiao ◽  
Yangmin Qiu ◽  
Jie Ding ◽  
Nana Luo ◽  
Hao Wang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Liver Toxicity ◽  
Nk Cell ◽  
Immune Therapy ◽  
Clinical Development ◽  
Cell Surface Receptor ◽  
Natural Ligand

AbstractExpression of the cell surface receptor CD137 has been shown to enhance anti-cancer T cell function via engagement with its natural ligand 4-1BBL. CD137 ligation with engineered ligands has emerged as a cancer immunotherapy strategy, yet clinical development of agonists has been hindered by either toxicity or limited efficacy. Here we show that a CD137/PD-1 bispecific antibody, IBI319, is able to overcome these limitations by coupling CD137 activation to PD-1-crosslinking. In CT26 and MC38 syngeneic mouse tumour models, IBI319 restricts T cell co-stimulation to PD-1-rich microenvironments, such as tumours and tumour-draining lymph nodes, hence systemic (liver) toxicity arising from generalised T cell activation is reduced. Besides limiting systemic T cell co-stimulation, the anti-PD-1 arm of IBI319 also exhibits checkpoint blockade functions, with an overall result of T and NK cell infiltration into tumours. Toxicology profiling in non-human primates shows that IBI319 is a well-tolerated molecule with IgG-like pharmacokinetic properties, thus a suitable candidate for further clinical development.

scholarly journals Abortive Proliferation of Rare T Cells Induced by Direct or Indirect Antigen Presentation by Rare B Cells In Vivo

1998 ◽  
Vol 187 (10) ◽  
pp. 1611-1621 ◽  
Author(s):  
Sarah E. Townsend ◽  
Christopher C. Goodnow
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Antigen Presentation ◽  
Cell Fate ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Presenting Cells ◽  
Antigen Presenting

Antigen-specific B cells are implicated as antigen-presenting cells in memory and tolerance responses because they capture antigens efficiently and localize to T cell zones after antigen capture. It has not been possible, however, to visualize the effect of specific B cells on specific CD4+ helper T cells under physiological conditions. We demonstrate here that rare T cells are activated in vivo by minute quantities of antigen captured by antigen-specific B cells. Antigen-activated B cells are helped under these conditions, whereas antigen-tolerant B cells are killed. The T cells proliferate and then disappear regardless of whether the B cells are activated or tolerant. We show genetically that T cell activation, proliferation, and disappearance can be mediated either by transfer of antigen from antigen-specific B cells to endogenous antigen-presenting cells or by direct B–T cell interactions. These results identify a novel antigen presentation route, and demonstrate that B cell presentation of antigen has profound effects on T cell fate that could not be predicted from in vitro studies.

scholarly journals Complete differentiation of CD8+ T cells activated locally within the transplanted liver

2006 ◽  
Vol 203 (2) ◽  
pp. 437-447 ◽  
Author(s):  
Ingo Klein ◽  
Ian Nicholas Crispe
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Underlying Mechanism ◽  
Color Flow ◽  
Antigen Presenting ◽  
Transplantation Model

The transplanted liver elicits systemic tolerance, and the underlying mechanism may also account for the persistence of liver infections, such as malaria and viral hepatitis. These phenomena have led to the hypothesis that antigen presentation within the liver is abortive, leading to T cell tolerance or apoptosis. Here we test this hypothesis in an optimized orthotopic liver transplantation model. In direct contradiction to this model, the liver itself induces full CD8+ T cell activation and differentiation. The effects of microchimerism were neutralized by bone marrow transplantation in the liver donor, and the lack of liver-derived antigen-presenting cells was documented by eight-color flow cytometry and by sensitive functional assays. We conclude that local antigen presentation cannot explain liver tolerance. On the contrary, the liver may be an excellent priming site for naive CD8+ T cells.

scholarly journals Dendritic cells process synthetic long peptides better than whole protein, improving antigen presentation and T-cell activation

2013 ◽  
Vol 43 (10) ◽  
pp. 2554-2565 ◽  
Author(s):  
Rodney A. Rosalia ◽  
Esther D. Quakkelaar ◽  
Anke Redeker ◽  
Selina Khan ◽  
Marcel Camps ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Synthetic Long Peptides ◽  
Better Than

scholarly journals Expression and functional significance of an additional ligand for CTLA-4

1993 ◽  
Vol 90 (23) ◽  
pp. 11054-11058 ◽  
Author(s):  
D J Lenschow ◽  
G H Su ◽  
L A Zuckerman ◽  
N Nabavi ◽  
C L Jellis ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Costimulatory Molecule ◽  
T Cell Proliferation ◽  
Antigen Presenting

Effective T-cell activation requires antigen/major histocompatibility complex engagement by the T-cell receptor complex in concert with one or more costimulatory molecules. Recent studies have suggested that the B7 molecule, expressed on most antigen presenting cells, functions as a costimulatory molecule through its interaction with CD28 on T cells. Blocking the CD28/B7 interaction with CTLA4Ig inhibits T-cell activation in vitro and induces unresponsiveness. We demonstrate that another molecule(s), termed B7-2, is expressed constitutively on dendritic cells, is differentially regulated on B cells, and costimulates naive T cells responding to alloantigen. B7-2 is up-regulated by lipopolysaccharide in < 6 hr and is maximally expressed on the majority of B cells by 24 hr. In contrast, B7 is detected only on a subset of activated B cells late (48 hr) after stimulation. In addition, Con A directly induces B7-2 but not B7 expression on B cells. Finally, although both anti-B7 monoclonal antibodies and CTLA4Ig blocked T-cell proliferation to antigen-expressing B7 transfectants, only CTLA4Ig had any significant inhibitory effect on T-cell proliferation to antigens expressed on natural antigen presenting cells, such as dendritic cells. Thus, B7 is not the only costimulatory molecule capable of initiating T-cell responses since a second ligand, B7-2, can provide a necessary second signal for T-cell activation.

scholarly journals Acquisition and presentation of follicular dendritic cell–bound antigen by lymph node–resident dendritic cells

2010 ◽  
Vol 208 (1) ◽  
pp. 135-148 ◽  
Author(s):  
Megan L. McCloskey ◽  
Maria A. Curotto de Lafaille ◽  
Michael C. Carroll ◽  
Adrian Erlebacher
Keyword(s):  
Dendritic Cells ◽  
Lymph Node ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Immune Complexes ◽  
Cell Activation ◽  
Follicular Dendritic Cell ◽  
Affinity Maturation ◽  
Follicular Dendritic

Follicular dendritic cells (DCs [FDCs]) are prominent stromal cell constituents of B cell follicles with the remarkable ability to retain complement-fixed antigens on their cell surface for extended periods of time. These retained immune complexes have long been known to provide the antigenic stimulus that drives antibody affinity maturation, but their role in cellular immunity has remained unclear. In this study, we show that FDC-retained antigens are continually sampled by lymph node–resident DCs for presentation to CD8 T cells. This novel pathway of antigen acquisition was detectable when FDCs were loaded with purified antigens bound into classical antigen–antibody immune complexes, as well as after pregnancy, when they are loaded physiologically with antigens associated with the complement-fixed microparticles released from the placenta into maternal blood. In both cases, ensuing antigen presentation was profoundly tolerogenic, as it induced T cell deletion even under inflammatory conditions. These results significantly broaden the scope of FDC function and suggest new ways that the complement system and persistent antigen presentation might influence T cell activation and the maintenance of peripheral immune tolerance.

scholarly journals Human CD14hi monocytes and myeloid dendritic cells provide a cell contact–dependent costimulatory signal for early CD40 ligand expression

Blood ◽  
2011 ◽  
Vol 117 (5) ◽  
pp. 1585-1594 ◽  
Author(s):  
Sagarika Chakrabarty ◽  
James T. Snyder ◽  
Jijia Shen ◽  
Hooman Azmi ◽  
Paul Q. Hu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Myeloid Dendritic Cells ◽  
A Cell ◽  
Cd40l Expression ◽  
Antigen Presenting

Abstract CD40L on CD4+ T cells plays a vital role in the activation of antigen-presenting cells, thus catalyzing a positive feedback loop for T-cell activation. Despite the pivotal juxtaposition of CD40L between antigen-presenting cells and T-cell activation, only a T-cell receptor stimulus is thought to be required for early CD40L surface expression. We show, for the first time, that CD40L expression on peripheral blood CD4+ T cells is highly dependent on a cell-cell interaction with CD14hiCD16− monocytes. Interactions with ICAM-1, LFA-3, and to a lesser extent CD80/CD86 contribute to this enhancement of CD40L expression but are not themselves sufficient. The contact-mediated increase in CD40L expression is dependent on new mRNA and protein synthesis. Circulating myeloid dendritic cells also possess this costimulatory activity. By contrast, CD14loCD16+ monocytes, plasmacytoid dendritic cells, B-cell lymphoma lines, and resting, activated, and Epstein-Barr virus–immortalized primary B cells all lack the capacity to up-regulate early CD40L. The latter indicates that a human B cell cannot activate its cognate T cell to deliver CD40L-mediated help. This finding has functional implications for the role of biphasic CD40L expression, suggesting that the early phase is associated with antigen-presenting cell activation, whereas the late phase is related to B-cell activation.

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