<img height="1" width="1" src="https://www.facebook.com/tr?id=1582471781774081&amp;ev=PageView &amp;noscript=1">
  • Menu
  • crown-logo-symbol-1-400x551

Find it Quickly

Get Started

Select the option that best describes what you are looking for

  • Services
  • Models
  • Scientific Information

Search Here For Services

Click Here to Start Over

Search Here For Models

Click Here to Start Over

Search Here For Scientific Information

Click Here to Start Over

In Vitro

Boost oncology drug discovery with XenoBase®, featuring the largest cell line selection and exclusive 3D organoid models. Benefit from OrganoidXplore™ and OmniScreen™ for rapid, in-depth analysis.

Learn More

In Vivo

Enhance drug development with our validated in vivo models, in vitro/ex vivo assays, and in silico modeling. Tailored solutions to optimize your candidates.

Learn More

Tissue

Experience ISO-certified biobanking quality. Access top biospecimens from a global clinical network, annotated by experts for precise research.

Learn More

Biomarkers and Bioanalysis

Leverage our global labs and 150+ scientists for fast, tailored project execution. Benefit from our expertise, cutting-edge tech, and validated workflows for reliable data outcomes.

Learn More

Data Science and Bioinformatics

Harness your data and discover biomarkers with our top bioinformatics expertise. Maximize data value and gain critical insights to accelerate drug discovery and elevate projects.

Learn More

KRAS

Accelerate innovative cancer treatments with our advanced models and precise drug screening for KRAS mutations, efficiently turning insights into clinical breakthroughs.

Learn More

EGFR

Advance translational pharmacology with our diverse pre-clinical models, robust assays, and data science-driven biomarker analysis, multi-omics, and spatial biology.

Learn More

Drug Resistance

Our suite integrates preclinical solutions, bioanalytical read-outs, and multi-omics to uncover drug resistance markers and expedite discovery with our unique four-step strategy.

Learn More

Patient Tissue

Enhance treatments with our human tumor and mouse models, including xenografts and organoids, for accurate cancer biology representation.

Learn More

Bioinformatics

Apply the most appropriate in silico framework to your pharmacology data or historical datasets to elevate your study design and analysis, and to improve your chances of clinical success.

Learn More

Biomarker Analysis

Integrate advanced statistics into your drug development projects to gain significant biological insight into your therapeutic candidate, with our expert team of bioinformaticians.

Learn More

CRISPR/Cas9

Accelerate your discoveries with our reliable CRISPR solutions. Our global CRISPR licenses cover an integrated drug discovery platform for in vitro and in vivo efficacy studies.

Learn More

Genomics

Rely on our experienced genomics services to deliver high quality, interpretable results using highly sensitive PCR-based, real-time PCR, and NGS technologies and advanced data analytics.

Learn More

In Vitro High Content Imaging

Gain more insights into tumor growth and disease progression by leveraging our 2D and 3D fluorescence optical imaging.

Learn More

Mass Spectrometry-based Proteomics

Next-generation ion mobility mass spectrometry (MS)-based proteomics services available globally to help meet your study needs.

Learn More

Ex Vivo Patient Tissue

Gain better insight into the phenotypic response of your therapeutic candidate in organoids and ex vivo patient tissue.

Learn More

Spatial Multi-Omics Analysis

Certified CRO services with NanoString GeoMx Digital Spatial Profiling.

Learn More

Biomarker Discovery

De-risk your drug development with early identification of candidate biomarkers and utilize our biomarker discovery services to optimize clinical trial design.

Learn More

DMPK Services

Rapidly evaluate your molecule’s pharmaceutical and safety properties with our in vivo drug metabolism and pharmacokinetic (DMPK) services to select the most robust drug formulations.

Learn More

Efficacy Testing

Explore how the novel HuGEMM™ and HuCELL™ platforms can assess the efficacy of your molecule and accelerate your immuno-oncology drug discovery programs.

Learn More

Laboratory Services

Employ cutting-edge multi-omics methods to obtain accurate and comprehensive data for optimal data-based decisions.

Learn More

Pharmacology & Bioanalytical Services

Leverage our suite of structural biology services including, recombinant protein expression and protein crystallography, and target validation services including RNAi.

Learn More

Screens

Find the most appropriate screen to accelerate your drug development: discover in vivo screens with MuScreen™ and in vitro cell line screening with OmniScreen™.

Learn More

Toxicology

Carry out safety pharmacology studies as standalone assessments or embedded within our overall toxicological profiling to assess cardiovascular, metabolic and renal/urinary systems.

Learn More

Our Company

Global CRO in California, USA offering preclinical and translational oncology platforms with high-quality in vivo, in vitro, and ex vivo models.

Learn More

Our Purpose

Learn more about the impact we make through our scientific talent, high-quality standards, and innovation.

Learn More

Our Responsibility

We build a sustainable future by supporting employee growth, fostering leadership, and exceeding customer needs. Our values focus on innovation, social responsibility, and community well-being.

Learn More

Meet Our Leadership Team

We build a sustainable future by fostering leadership, employee growth, and exceeding customer needs with innovation and social responsibility.

Learn More

Scientific Advisory Board

Our Scientific Advisory Board of experts shapes our strategy and ensures top scientific standards in research and development.

Learn More

News & Events

Stay updated with Crown Bioscience's latest news, achievements, and announcements. Check our schedule for upcoming events and plan your visit.

Learn More

Career Opportunities

Join us for a fast-paced career addressing life science needs with innovative technologies. Thrive in a respectful, growth-focused environment.

Learn More

Scientific Publications

Access our latest scientific research and peer-reviewed articles. Discover cutting-edge findings and insights driving innovation and excellence in bioscience.

Learn More

Resources

Discover valuable insights and curated materials to support your R&D efforts. Explore the latest trends, innovations, and expertly curated content in bioscience.

Learn More

Blogs

Explore our blogs for the latest insights, research breakthroughs, and industry trends. Stay educated with expert perspectives and in-depth articles driving innovation in bioscience.

Learn More

  • Platforms
  • Target Solutions
  • Technologies
  • Service Types

ICOS: Immunostimulatory or Immunosuppressive Target?

Dual roles of ICOS pathway, T cell receptor target in immunotherapy

Dual roles of ICOS pathway, T cell receptor target in immunotherapyThe rise of immunotherapy has brought many new targets to the forefront of oncology drug development. One promising new avenue of investigation is ICOS, an immune checkpoint expressed on activated T cells, which has opposing functions in sustaining T cell activation and in Treg suppressive activity.

This introductory review explores the dual roles of ICOS and how these can be targeted via different immunotherapeutic approaches.

ICOS: A Member of the CD28/CTLA-4 Family, Expressed on Activated T Cells

The T cell-specific cell-surface receptors CD28 and CTLA-4 are important regulators of the immune system:

  • CD28 potently enhances T cell functions that are essential for an effective antigen-specific immune response
  • The homologous CTLA-4 counteracts CD28-mediated costimulatory signals and impairs T cell activation, thereby preventing an otherwise fatal overstimulation of the lymphoid system.

A third member of the CD28/CTLA-4 family is the inducible co-stimulator (ICOS). ICOS is a homodimeric protein which is expressed on activated T cells, and only at low levels on resting, naïve T cells. ICOS binds specifically to its ligand (ICOS-L), also known as B7-related protein-1 (B7RP-1), which is expressed constitutively on B cells.

ICOS Signaling, T Cell Activation, and Effector Functions

During the immune response, T cells are optimally activated in secondary lymphoid tissues to properly migrate into areas of inflamed tissue. Upon antigen recognition, via the T cell receptor (TCR)/CD3 antigen (CD3) complex, a second co-stimulatory signal from APCs is necessary for the activation of naive T cells.

T cell activation induces co-stimulatory molecules, including the ICOS/Activation-Inducible Lymphocyte Immunomediatory Molecule (AILIM). ICOS-mediated signaling contributes mainly to the regulation of activated T cells and to effector T cell functions, and the potency of ICOS is enhanced following its ligation to ICOS-L.

ICOS and Treg Homeostasis

ICOS is highly expressed on tonsillar T cells, which are closely associated with B cells in the apical light zone of germinal centers, where terminal B cell maturation occurs. In the absence of ICOS, germinal center formation is impaired and immunoglobulin class switching is defective (1,2).

In addition to providing help for B cells, and acting as a key costimulatory signal for T cell proliferation and survival, ICOS also regulates development and response of T follicular helper (Tfh), Th1, Th2, and Th17 cells while playing roles in the maintenance of memory effector T cells and regulatory T cells (Treg) homeostasis.

Dual ICOS Role Provides Multiple Opportunities to Enhance Antitumor Immunity

Due to its dual role in sustaining T cell activation and effector functions, as well as its connection with Treg suppressive activity, targeting ICOS/ICOS-L represents an attractive approach to enhancing antitumor immunity.

In the clinic, downregulation of ICOS has been shown in colon cancer patients, while the expression of ICOS in tumors was shown to be associated with greater survival in melanoma patients.

In opposition, it has been demonstrated that the selective expression of ICOS on a “hyperactivated” Treg intra-tumoral population strongly inhibited T cell response through IL-10-mediated APC suppression.

Moreover, it has been shown that ICOS-L is expressed on both cultured and freshly isolated melanoma cells from Stage IV melanoma patients, and can provide co-stimulation through ICOS for the activation and expansion of Tregs in the tumor microenvironment. This provides another mechanism of escape from immune surveillance.

Both Agonistic and Antagonistic ICOS Antibodies Under Development

Both antagonist and agonist antibodies are of interest in targeting the ICOS/ICOS-L pathway for cancer treatment.

Currently, two agonists and one antagonist mAb are being evaluated in Phase I/II trials. Efficacy, safety, and combination strategies with anti-ICOS agonists or antagonists have yet to be specified.

ICOS Agonist mAbs:

  • GSK3359609 (GlaxoSmithKline) is being evaluated in a Phase I open label study, both alone and in combination with pembrolizumab in subjects with selected advanced solid tumors (INDUCE-1, NCT02723955).
  • JTX-2011 (Jounce Therapeutics) is being evaluated in a Phase I/II, open label study, alone or in combination with nivolumab in subjects with advanced solid tumors (ICONIC, NCT02904226)

ICOS Antagonist mAbs:

  • • MEDI-570 (Medimmune, NCT02520791) is being evaluated in a Phase I trial in patients with relapsed/refractory peripheral T cell lymphoma (PTCL) follicular variants and angioimmunoblastic T cell lymphoma (AITL). MEDI-570 is a human IgG1κ mAb directed against the ligand-binding domain of ICOS, which can promote antibody-dependent cellular cytotoxicity (ADCC) activity against ICOS+ T cells.

As with all new immuno-oncology targets, a thorough understanding of ICOS signaling and its multiple T cell roles will help decide which therapeutic routes and options may bring the most benefit to patients.

References and Further Reading:

  1. Breitfeld et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med 2000; 192(11):1545-52.
  2. Schaerli et al. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med 2000;192(11):1553-62.

Related Posts