Tumor-Reactive CD8+ T Cells in Metastatic Gastrointestinal Cancer Refractory to Chemotherapy
To evaluate whether patients with metastatic gastrointestinal adenocarcinomas refractory to chemotherapy harbor tumor-reactive cytotoxic T cells. Expansion of CD8(+) tumor-infiltrating lymphocytes (TIL) and cancer cell lines was attempted from gastrointestinal cancer metastases in 16 consecutive pat...
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Veröffentlicht in: | Clinical cancer research 2014-01, Vol.20 (2), p.331-343 |
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Zusammenfassung: | To evaluate whether patients with metastatic gastrointestinal adenocarcinomas refractory to chemotherapy harbor tumor-reactive cytotoxic T cells.
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.
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.
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. |
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ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-13-1736 |