Data from Tumor-Reactive CD8<sup>+</sup> T Cells in Metastatic Gastrointestinal Cancer Refractory to Chemotherapy

Abstract

<div>Abstract<p><b>Purpose:</b> To evaluate whether patients with metastatic gastrointestinal adenocarcinomas refractory to chemotherapy harbor tumor-reactive cytotoxic T cells.</p><p><b>Experimental Design:</b> Expansion of CD8<sup>+</sup> 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.</p><p><b>Results:</b> 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<sup>+</sup> TIL from 3 of these 5 patients. In a patient with gastric cancer liver metastases, the repertoire of CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> TIL repertoire. TCRs isolated from these clones recognized epitopes restricted by HLA-A*0201. In a third patient, CD8<sup>+</sup> TIL reactivity was progressively lost against an autologous colon cancer cell line that displayed loss of HLA haplotype.</p><p><b>Conclusions:</b> 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<sup>+</sup> TIL at the molecular level. <i>Clin Cancer Res; 20(2); 331–43. ©2013 AACR</i>.</p></div>