Genetic modification of T cells with IL-21 enhances antigen presentation and generation of central memory tumor-specific cytotoxic T-lymphocytes.
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.
Kaka
Anjum S
AS
Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX, USA.
Shaffer
Donald R
DR
Hartmaier
Ryan
R
Hartmeier
Ryan
R
Leen
Ann M
AM
Lu
An
A
Bear
Adham
A
Rooney
Cliona M
CM
Foster
Aaron E
AE
D017951:Antigen Presentation / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D016130:Immunophenotyping; D007378:Interleukins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020014:K562 Cells; D016086:Lentivirus / Q000235:genetics; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D000098546:Interleukin-21
D007378:Interleukins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human; D000098546:Interleukin-21