title: Phenotype and function of T cells infiltrating visceral metastases from gastrointestinal cancers and melanoma: implications for adoptive cell transfer therapy.
abstract: Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate cancer regression in patients with metastatic melanoma, but whether this approach can be applied to common epithelial malignancies remains unclear. In this study, we compared the phenotype and function of TILs derived from liver and lung metastases from patients with gastrointestinal (GI) cancers (n = 14) or melanoma (n = 42). Fewer CD3(+) T cells were found to infiltrate GI compared with melanoma metastases, but the proportions of CD8(+) cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to ~50 × 10(9) T cells on average was obtained for all patients with GI cancer and melanoma. From GI tumors, however, TIL outgrowth in high-dose IL-2 yielded 22 ± 1.4% CD3(+)CD8(+) cells compared with 63 ± 2.4% from melanoma (p < 0.001). IFN-γ ELISA demonstrated MHC class I-mediated reactivity of TIL against autologous tumor in 5 of 7 GI cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class I-mediated up-regulation of CD137 (4-1BB) expression on CD8(+) cells suggested that 0-3% of TILs expanded from GI cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Turcotte
authors.forename: Alena
authors.initials: A
authors.lastname: Gros
authors.forename: Katherine
authors.initials: K
authors.lastname: Hogan
authors.forename: Eric
authors.initials: E
authors.lastname: Tran
authors.forename: Christian S
authors.initials: CS
authors.lastname: Hinrichs
authors.forename: John R
authors.initials: JR
authors.lastname: Wunderlich
authors.forename: Mark E
authors.initials: ME
authors.lastname: Dudley
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D005260:Female; D005434:Flow Cytometry; D005770:Gastrointestinal Neoplasms / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000276:immunology / Q000473:pathology; D010641:Phenotype; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
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