title: Functional CD8+ T cells infiltrate into nonsmall cell lung carcinoma.
abstract: Infiltration of CD3(+)CD8(+) cytotoxic T cells was analyzed by multiparameter confocal laser microscopy in a panel of 16 randomly selected stage I nonsmall cell lung carcinomas. T-cell infiltration was observed in the stroma (range 57-2,093 T cells/mm(2)) but also in the tumor epithelium (range 21-892 T cells/mm(2)) and showed wide variation between individual tumors. Interestingly, a significantly higher percentage of CD3(+)CD8(+) T cells was detected in the tumor epithelium compared to the stroma illustrating that cytotoxic T cells may preferentially migrate into tumor epithelium. Aberrant HLA class I antigen expression was observed in 69% of the nonsmall-cell lung carcinoma (NSCLC) tumors. One tumor of a squamous cell lung carcinoma patient with the highest number of tumor infiltrating CD3(+) and CD3(+)CD8(+) cells was studied in detail and the majority (90%) of these cells were shown to be functionally activated granzyme B-positive cytotoxic T cells. DNA oligotyping of a lung carcinoma cell line established from this tumor revealed loss of one HLA haplotype corresponding with a translocation involving chromosome 6, as observed by COBRA-FISH. HLA class I-restricted tumor specific T cells could be isolated from PBMC. One further characterized cytotoxic CD8(+) T cell clone, that released TNF-alpha, IFN-gamma, and granzyme B upon co-incubation with the autologous tumor cells, was shown to be restricted by the remaining HLA-A11 allele, which was also shown to be expressed in the tumor tissue. Our data indicate that, despite HLA-haplotype loss a vigorous antitumor immune response mediated by CD8(+ )T-cells can be present in NSCLC offering possibilities for specific immunotherapy.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands. e.verdegaal@lumc.nl
authors.forename: Elizabeth M E
authors.initials: EM
authors.lastname: Verdegaal
authors.forename: Conny
authors.initials: C
authors.lastname: Hoogstraten
authors.forename: Maro H
authors.initials: MH
authors.lastname: Sandel
authors.forename: Peter J K
authors.initials: PJ
authors.lastname: Kuppen
authors.forename: Antoinette A T P
authors.initials: AA
authors.lastname: Brink
authors.forename: Frans H J
authors.initials: FH
authors.lastname: Claas
authors.forename: Michael C B
authors.initials: MC
authors.lastname: Gorsira
authors.forename: J Frans
authors.initials: JF
authors.lastname: Graadt van Roggen
authors.forename: Susanne
authors.initials: S
authors.lastname: Osanto
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000276:immunology*; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I