Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 61, Issue 3, Pages 385-396Publisher
SPRINGER
DOI: 10.1007/s00262-011-1111-6
Keywords
Antigen presentation; gamma delta T cells; Tumor antigens; Self-antigens; Cellular therapy
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Funding
- Deutsche Krebshilfe
- Wilhelm-Sander-Stiftung
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Specific cellular immunotherapy of cancer requires efficient generation and expansion of cytotoxic T lymphocytes (CTLs) that recognize tumor-associated self-antigens. Here, we investigated the capacity of human gamma delta T cells to induce expansion of CD8+ T cells specific for peptides derived from the weakly immunogenic tumor-associated self-antigens PRAME and STEAP1. Coincubation of aminobisphosphonate-stimulated human peripheral blood-derived gamma delta T cells (V gamma 9+V delta 2+), loaded with HLA-A*02-restricted epitopes of PRAME, with autologous peripheral blood CD8+ T cells stimulated the expansion of peptide-specific cytolytic effector memory T cells. Moreover, peptide-loaded gamma delta T cells efficiently primed antigen-naive CD45RA+ CD8+ T cells against PRAME peptides. Direct comparisons with mature DCs revealed equal potency of gamma delta T cells and DCs in inducing primary T-cell responses and peptide-specific T-cell activation and expansion. Antigen presentation by gamma delta T-APCs was not able to overcome the limited capacity of peptide-specific T cells to interact with targets expressing full-length antigen. Importantly, T cells with regulatory phenotype (CD4+CD25hiFoxP3+) were lower in cocultures with gamma delta T cells compared to DCs. In summary, bisphosphonate-activated gamma delta T cells permit generation of CTLs specific for weakly immunogenic tumor-associated epitopes. Exploiting this strategy for effective immunotherapy of cancer requires strategies that enhance the avidity of CTL responses to allow for efficient targeting of cancer.
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