Modulating Co-Stimulation During Antigen Presentation to Enhance Cancer Immunotherapy

Liechtenstein, Therese; Dufait, Inès; Lanna, Alessio; Breckpot, Karine; Escors, David

doi:10.2174/187152212802001875

Cited by 44 publications

(64 citation statements)

References 192 publications

(175 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Costimulatory signals (e.g., CD80/86) and cytokines are also necessary to induce a strong tumor-specific CTL response 16 . At 24 h post immunization with OVA-PC7A NP, inguinal LNs increased in size compared to OVA alone (Supplementary Fig.…”

mentioning

confidence: 99%

A STING-activating nanovaccine for cancer immunotherapy

et al. 2017

View full text Add to dashboard Cite

Generation of tumor-specific T cells is critically important for cancer immunotherapy1,2. A major challenge in achieving a robust T cell response is the spatio-temporal orchestration of antigen cross-presentation in antigen presenting cells (APCs) with innate stimulation. Here we report a minimalist nanovaccine by a simple physical mixture of an antigen with a synthetic polymeric nanoparticle, PC7A NP, which generated a strong cytotoxic T cell response with low systemic cytokine expression. Mechanistically, PC7A NP achieved efficient cytosolic delivery of tumor antigens to APCs in draining lymph nodes leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes. This effect was dependent on STING but not Toll-like receptor or MAVS pathway. Nanovaccine produced potent tumor growth inhibition in melanoma, colon cancer, and human papilloma virus-E6/E7 tumor models. Combination of PC7A nanovaccine with an anti-PD-1 antibody showed great synergy with 100% survival over 60 days in a TC-1 tumor model. Rechallenging of these tumor-free animals with TC-1 cells led to complete inhibition of tumor growth, suggesting generation of long-term antitumor memory. The STING-activating nanovaccine offers a simple, safe and robust strategy in boosting anti-tumor immunity for cancer immunotherapy.

show abstract

mentioning

confidence: 99%

A STING-activating nanovaccine for cancer immunotherapy

et al. 2017

View full text Add to dashboard Cite

show abstract

“…One of such is antigen presentation, the process by which T cells recognise their cognate antigens presented to them by APCs, such as dendritic cells (DCs) [3]. T cells recognise antigens by binding of their T cell receptor (TCR) with complexes between the antigenic peptides and MHC molecules (p-MCH), present on the surface of APCs [9]. However, for the T cell to be effectively activated, at least two different types of interactions have to occur in the immunological synapse [20,21].…”

Section: Antigen Presentation To T Cells and T Cell Differentiationmentioning

confidence: 99%

“…Depending on the particular pathogen encountered by DCs and other APCs, these APCs will secrete different cytokines while undertaking antigen presentation to T cells. The particular cytokine combinations (signal 3) will drive the differentiation profile of T cells while signals 1 and 2 are being delivered [9,[25][26][27] (Figure 1). T cells then differentiate to specific types of effector cells such as cytotoxic CD8 and CD4 T cells, and CD4 T helper (Th) cells.…”

Section: Antigen Presentation To T Cells and T Cell Differentiationmentioning

confidence: 99%

“…To counteract the immune attack, cancer cells actively inhibit and escape from the immune system. They achieve this by a variety of mechanisms, including low expression of major histocompatibility molecules (MHC molecules associate to antigen peptides for antigen presentation to T cells), secretion of potent immunosuppressive cytokines, and expression of T cell inhibitory molecules such as some members of the B7 family of molecules (PD-L1, PD-L2, B7-H3, VISTA) [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…Some examples for clinical use are Rituximab (B cell-depleting antibody used for leukaemia, rheumatoid arthritis, lupus), Infliximab (TNF-alpha-neutralising antibody used in rheumatic diseases) or Ipilimumab (blocking/depleting anti-CTLA4 antibody, used in cancer) [15][16][17][18][19]. In the case of cancer immunotherapy, these antibodies usually interfere with T cell inhibitory interactions, such as CTLA4 on the surface of T cells with CD80/CD86 on the surface of professional antigen presenting cells (APCs), or in an analogous way, PD-1 with PD-L1/PD-L2 [9].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Signaling Mechanisms that Balance Anti-viral, Auto-reactive, and Antitumor Potential of Low Affinity T Cells

Hebeisen¹,

Rufer²,

Oberle³

et al. 2013

J Clin Cell Immunol

View full text Add to dashboard Cite

For T cell activation, three signals have to be provided from the antigen presenting cell; Signal 1 (antigen recognition), signal 2 (co-stimulation) and signal 3 (cytokine priming). Blocking negative co-stimulation during antigen presentation to T cells is becoming a promising therapeutic strategy to enhance cancer immunotherapy. Here we will focus on interference with PD-1/PD-L1 negative co-stimulation during antigen presentation to T cells as a therapeutic approach. We will discuss the potential mechanisms and the therapeutic consequences by which interference/inhibition with this interaction results in anti-tumour immunity. Particularly, we will comment on whether blocking negative co-stimulation provides differentiation signals to T cells undergoing antigen presentation. A major dogma in immunology states that T cell differentiation signals are given by cytokines and chemokines (signal 3) rather than co-stimulation (signal 2). We will discuss whether this is the case when blocking PD-L1/PD-1 negative co-stimulation.

show abstract

Autocrine activation of canonical BMP signaling regulates PD‐L1 and PD‐L2 expression in human dendritic cells

et al. 2014

View full text Add to dashboard Cite

Bone morphogenetic proteins (BMPs) are multifunctional growth factors regulating differentiation and proliferation in numerous systems including the immune system. Previously, we described that the BMP signaling pathway is functional in human monocytederived dendritic cells (MoDCs), which were found to express both the specific receptors and the Smad proteins required for signal transduction. In this study, we provide evidence that human MoDCs produce BMP-4 and that this production is increased over the maturation process as is BMP signal transduction. When DCs are matured in the presence of an inhibitor of the BMP pathway, the expression of the maturation markers PD-L1 and PD-L2 is reduced, while cytokine production is not affected. As a result, these mature DCs present an augmented ability to stimulate both T cells and NK cells. Eventually, the inhibition of BMP signaling during maturation causes a reduced expression of IRF-1, a transcription factor that positively regulates the expression of PD-L1 and PD-L2. The present study indicates that the BMP signaling pathway regulates PD-L1 and PD-L2 expression in human MoDCs during the maturation process, probably through the IRF-1 transcription factor, and also points out that the manipulation of BMP signaling might considerably improve the immunogenicity of MoDCs used in immunotherapy.Keywords: Bone morphogenetic proteins r Dendritic cells r Dorsomorphin r PD-L1 r PD-L2 Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionBone morphogenetic proteins (BMPs) are members of the TGF-β superfamily [1]. The BMP signaling pathway is initiated when dimeric ligands associate with type I and type II BMP receptors, which are transmembrane serine/threonine kinases, forming a multimeric receptor-ligand complex. Within this complex, Correspondence: Dr. Alberto Varas e-mail: avaras@bio.ucm.es type I BMP receptors are phosphorylated by ligand-bound type II BMP receptors and then phosphorylate and activate some components of the Smad protein family, Smad1, 5 and 8, called BMP receptor-regulated Smads (BR-Smads) [1,2]. Subsequently, BR-Smads form complexes with the common partner Smad4 and translocate into the nucleus, where they regulate the transcription of BMP target genes, including Id proteins and Runx * These authors contributed equally to this work.www.eji-journal.eu1032 Víctor G. Martínez et al. Eur. J. Immunol. 2014. 44: 1031-1038 transcription factors [1]. In addition to this canonical signaling pathway, the activated BMP receptor complexes may initiate noncanonical Smad-independent pathways, notably via MAP kinases [1,2]. BMPs were originally identified as osteoinductive cytokines that promote bone and cartilage formation in vivo, but now are considered multifunctional proteins involved in the development of virtually all organs and the maintenance and renewal of several adult tissues [1,3,4]. In the immune system, BMPs inhibit human B-cell lymphopoieis in the bone marrow [5], and in the thymus, BMP...

show abstract

Modulating Co-Stimulation During Antigen Presentation to Enhance Cancer Immunotherapy

Cited by 44 publications

References 192 publications

A STING-activating nanovaccine for cancer immunotherapy

A STING-activating nanovaccine for cancer immunotherapy

Signaling Mechanisms that Balance Anti-viral, Auto-reactive, and Antitumor Potential of Low Affinity T Cells

Autocrine activation of canonical BMP signaling regulates PD‐L1 and PD‐L2 expression in human dendritic cells

Contact Info

Product

Resources

About