Genetic modification of T cells with IL-21 enhances antigen presentation and generation of central memory tumor-specific cytotoxic T-lymphocytes.

Abstract

An optimized antigen-presenting cell for tumor immunotherapy should produce a robust antigen specific cytotoxic T lymphocytes (CTL) response to tumor-associated antigens, which can persist in vivo and expand on antigen reencounter. Interleukin (IL)-21 synergizes with other gamma-chain cytokines to enhance the frequency and cytotoxicity of antigen-specific CTL. As T cells themselves may serve as effective antigen-presenting cells (T antigen-presenting cells; TAPC) and may be useful in vivo as cellular vaccines, we examined whether CD8(+) T cells genetically modified to produce IL-21 could induce immune responses to tumor associated antigen peptides in healthy human leukocyte antigen-A2(+) donors. We found that IL-21 modified TAPC enhanced both the proliferation and survival of MART-1 specific CD8(+) T cells, which were enriched by >8-fold over cultures with control nontransgenic TAPC. MART-1-specific CTL produced interferon-gamma in response to cognate peptide antigen and killed primary tumor cells expressing MART-1 in a major histocompatibility complex restricted manner. IL-21 modified TAPC similarly enhanced generation of functional CTL against melanoma antigen gp100 and the B-cell chronic lymphocytic leukemia associated RHAMM antigen. Antigen-specific CTL generated using IL-21 gene-modified TAPC had a central memory phenotype characterized by CD45RA(-), CD44(high), CD27(high), CD28(high), CD62L(high), and IL-7 receptor-alpha(high), contrasting with the terminal effector phenotype of CTL generated in the absence of IL-21. Thus, TAPC stimulation in the presences of IL-21 enhances proliferation of tumor antigen-specific T cells and favors induction of a central memory phenotype, which may improve proliferation, survival, and efficacy of T-cell based therapies for the treatment of cancer.

• Authors: Anjum S Kaka, Donald R Shaffer, Ryan Hartmaier, Ryan Hartmeier, Ann M Leen, An Lu, Adham Bear, Cliona M Rooney, Aaron E Foster
• Journal: Journal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) Vol. 32 Issue 7 Pg. 726-36 (Sep 2009) ISSN: 1537-4513 [Electronic] United States
• PMID: 19561536 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Interleukins
• LEF1 protein, human
• Lymphoid Enhancer-Binding Factor 1
• T Cell Transcription Factor 1
• TCF7 protein, human
• interleukin-21

Topics

• Antigen Presentation (immunology)
• Antigen-Presenting Cells (immunology, metabolism)
• Apoptosis (drug effects)
• CD4-Positive T-Lymphocytes (drug effects, immunology, metabolism)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cytotoxicity, Immunologic (immunology)
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Gene Expression
• Humans
• Immunologic Memory (immunology)
• Immunophenotyping
• Interleukins (genetics, metabolism, pharmacology)
• K562 Cells
• Lentivirus (genetics)
• Lymphoid Enhancer-Binding Factor 1 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• T Cell Transcription Factor 1 (genetics, metabolism)
• T-Lymphocytes, Cytotoxic (immunology, metabolism)
• Transfection