Tumor-reactive CD8+ T cells in metastatic gastrointestinal cancer refractory to chemotherapy.
OBJECTIVE
To evaluate whether patients with metastatic gastrointestinal adenocarcinomas refractory to chemotherapy harbor tumor-reactive cytotoxic T cells.


METHODS
Expansion of CD8(+) tumor-infiltrating lymphocytes (TIL) and cancer cell lines was attempted from gastrointestinal cancer metastases in 16 consecutive patients for the study of antitumor immune recognition. Retroviral transduction of genes encoding T-cell receptors (TCR) was used to define HLA-restriction elements and specific reactivity.


RESULTS
TIL were expanded from metastases in all patients, and new tumor cell lines were generated in 5 patients. Autologous tumor recognition without cross-reactivity against allogeneic HLA-matched gastrointestinal tumors was found in CD8(+) TIL from 3 of these 5 patients. In a patient with gastric cancer liver metastases, the repertoire of CD8(+) TIL was dominated by cytolytic sister clones reactive to 2 out of 4 autologous cancer cell lines restricted by HLA-C*0701. From the same patient, a rare CD8(+) TIL clone with a distinct TCR recognized all four cancer cell lines restricted by HLA-B*4901. In a patient with bile duct cancer, two distinct antitumor cytolytic clones were isolated from a highly polyclonal CD8(+) TIL repertoire. TCRs isolated from these clones recognized epitopes restricted by HLA-A*0201. In a third patient, CD8(+) TIL reactivity was progressively lost against an autologous colon cancer cell line that displayed loss of HLA haplotype.


CONCLUSIONS
This study provides a basis for the development of immunotherapy for patients with advanced gastrointestinal malignancies by first establishing the presence of naturally occurring tumor-reactive CD8(+) TIL at the molecular level.
Authors' Affiliations: Surgery Branch and Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland.
Simon
S
Turcotte
Alena
A
Gros
Eric
E
Tran
Chyi-Chia R
CC
Lee
John R
JR
Wunderlich
Paul F
PF
Robbins
Steven A
SA
Rosenberg
D000328:Adult; D064592:Autografts; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D014161:Transduction, Genetic
D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell