Abstract
Effective elicitation of endogenous immunity is associated with improved prognosis for cancer patients. Clinical evidence in hematological and solid cancers shows that intratumoral injection of immunostimulatory genes primes and augments endogenous T cell responses. The ability of pro-inflammatory chemokines/cytokines to facilitate migration/activation of antigen-presenting cells (APC) and lymphocytes prompted our modeling of intratumoral delivery of a chemokine/cytokine combination for breast cancer treatment. Here, we demonstrate that expression of chemokine ligand 21 (CCL21) and interferon gamma (IFNγ) in tumors improves tumor specific T cell recruitment to tumor and activation in the tumor milieu. IFNγ and CCL21 were delivered into tumor cells via plasmids, and transfected cells were seeded to form spheroids on three-dimensional (3D) chitosan-alginate (CA) scaffolds. Co-expression of CCL21 and IFNγ, as evidenced by qRT-PCR and ELISA, induced increased recruitment, binding, and infiltration of anti-neu (p98) peptide specific T cells into the breast tumors as determined by SEM and immunofluorescence assays. The co-expression promoted recruitment of only p98 T cells, but not naïve T cells, demonstrating an antigen-restricted activation. Furthermore, the co-expression impacted T helper (Th) cell immunity, promoting an increase in secretion of pro-inflammatory Th-associated cytokine, tumor necrosis factor alpha (TNFα), and cytotoxic T lymphocyte (CTL)-associated protease, Granzyme B (GzB). Therefore, 3D CA scaffolds may be a useful breast cancer tumor microenvironment model to evaluate T cell function. Further characterization of CCL21-IFNγ mediated anti-tumor immunity will potentially benefit the development of chemokine/cytokine combination platforms as anti-cancer agents.
Keywords: Chemokines, cytokines, immunotherapy, intratumoral, microenvironment, scaffolds, T lymphocytes.
Anti-Cancer Agents in Medicinal Chemistry
Title:CCL21 and IFNγ Recruit and Activate Tumor Specific T cells in 3D Scaffold Model of Breast Cancer
Volume: 14 Issue: 2
Author(s): Vy Phan-Lai, Forrest M. Kievit, Stephen J. Florczyk, Kui Wang, Mary L. Disis and Miqin Zhang
Affiliation:
Keywords: Chemokines, cytokines, immunotherapy, intratumoral, microenvironment, scaffolds, T lymphocytes.
Abstract: Effective elicitation of endogenous immunity is associated with improved prognosis for cancer patients. Clinical evidence in hematological and solid cancers shows that intratumoral injection of immunostimulatory genes primes and augments endogenous T cell responses. The ability of pro-inflammatory chemokines/cytokines to facilitate migration/activation of antigen-presenting cells (APC) and lymphocytes prompted our modeling of intratumoral delivery of a chemokine/cytokine combination for breast cancer treatment. Here, we demonstrate that expression of chemokine ligand 21 (CCL21) and interferon gamma (IFNγ) in tumors improves tumor specific T cell recruitment to tumor and activation in the tumor milieu. IFNγ and CCL21 were delivered into tumor cells via plasmids, and transfected cells were seeded to form spheroids on three-dimensional (3D) chitosan-alginate (CA) scaffolds. Co-expression of CCL21 and IFNγ, as evidenced by qRT-PCR and ELISA, induced increased recruitment, binding, and infiltration of anti-neu (p98) peptide specific T cells into the breast tumors as determined by SEM and immunofluorescence assays. The co-expression promoted recruitment of only p98 T cells, but not naïve T cells, demonstrating an antigen-restricted activation. Furthermore, the co-expression impacted T helper (Th) cell immunity, promoting an increase in secretion of pro-inflammatory Th-associated cytokine, tumor necrosis factor alpha (TNFα), and cytotoxic T lymphocyte (CTL)-associated protease, Granzyme B (GzB). Therefore, 3D CA scaffolds may be a useful breast cancer tumor microenvironment model to evaluate T cell function. Further characterization of CCL21-IFNγ mediated anti-tumor immunity will potentially benefit the development of chemokine/cytokine combination platforms as anti-cancer agents.
Export Options
About this article
Cite this article as:
Phan-Lai Vy, Kievit M. Forrest, Florczyk J. Stephen, Wang Kui, Disis L. Mary and Zhang Miqin, CCL21 and IFNγ Recruit and Activate Tumor Specific T cells in 3D Scaffold Model of Breast Cancer, Anti-Cancer Agents in Medicinal Chemistry 2014; 14 (2) . https://dx.doi.org/10.2174/18715206113136660375
DOI https://dx.doi.org/10.2174/18715206113136660375 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
A Novel Triazole Derivative Drug Presenting In Vitro and In Vivo Anticancer Properties
Current Topics in Medicinal Chemistry The Role of Insulin Resistance and Hyperinsulinemia in Cancer Causation
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Methotrexate: A Drug of the Future in Ulcerative Colitis?
Current Drug Targets Research Highlight: Deoxyribonucleic Acid Based Nanotechnology
Micro and Nanosystems Therapeutic Targets for Management of Periodontitis and Diabetes
Current Pharmaceutical Design Src Family Nonreceptor Tyrosine Kinases as Molecular Targets for Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Clinical Importance and Potential Use of Small Molecule Inhibitors of Focal Adhesion Kinase
Anti-Cancer Agents in Medicinal Chemistry Substrates, Inhibitors and Activators of P-glycoprotein: Candidates for Radiolabeling and Imaging Perspectives
Current Topics in Medicinal Chemistry Small Non-Coding RNAs as Biomarkers
Recent Patents on Biomarkers Histidine Rich Glycoprotein, an Endogenous Regulator of Macrophage and Endothelial Biology
Current Angiogenesis (Discontinued) Recent Advances in Epitope Design for Immunotherapy of Cancer
Recent Patents on Anti-Cancer Drug Discovery Endocannabinoid System: A Promising Therapeutic Target for the Treatment of Haematological Malignancies?
Current Medicinal Chemistry Current Advances in Vehicles for Brain Gene Delivery
Current Gene Therapy Effect of Boswellia serrata on Rat Trachea Contractility In Vitro
The Natural Products Journal Therapeutic Potentials of Recently Identified PLD Inhibitors
Current Chemical Biology Flavonoids in Cancer Prevention
Anti-Cancer Agents in Medicinal Chemistry Respiratory Failure in Cancer Patients: Non-Infectious Complications of Antineoplastic Agents for Solid Tumors
Current Respiratory Medicine Reviews Emergence of Nanomedicine as Cancer Targeted Magic Bullets: Recent Development and Need to Address the Toxicity Apprehension
Current Drug Discovery Technologies Mechanisms of Drug-Induced Mitotic Catastrophe in Cancer Cells
Current Pharmaceutical Design Importance of Kier-Hall Topological Indices in the QSAR of Anticancer Drug Design
Current Computer-Aided Drug Design