Human Cancer Biology Tumor-Reactive CD8þ T Cells in Metastatic Gastrointestinal Cancer Refractory to Chemotherapy

Purpose: To evaluate whether patients with metastatic gastrointestinal adenocarcinomas refractory to chemotherapy harbor tumor-reactive cytotoxic T cells. ExperimentalDesign:ExpansionofCD8þ tumor-infiltrating lymphocytes (TIL) and cancer cell lineswas 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 frommetastases 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 CD8þ TIL from 3 of these 5 patients. In a patient with gastric cancer liver metastases, the repertoire of CD8þ 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 CD8þ TIL clone with a distinct TCR recognized all four cancer cell lines restricted byHLA-B 4901. In a patient with bile duct cancer, two distinct antitumor cytolytic clones were isolated from a highly polyclonal CD8þ TIL repertoire. TCRs isolated from these clones recognized epitopes restricted by HLA-A 0201. In a third patient, CD8þ TIL reactivity was progressively lost against an autologous colon cancer cell line that displayed loss of HLA