Tumor-reactive CD8+ T cells in metastatic gastrointestinal cancer refractory to chemotherapy.

Abstract

PURPOSE:

To evaluate whether patients with metastatic gastrointestinal adenocarcinomas refractory to chemotherapy harbor tumor-reactive cytotoxic T cells.

EXPERIMENTAL DESIGN:

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: Simon Turcotte, Alena Gros, Eric Tran, Chyi-Chia R Lee, John R Wunderlich, Paul F Robbins, Steven A Rosenberg
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 2 Pg. 331-43 (Jan 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24218514 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: ©2013 AACR.

Chemical References

• Histocompatibility Antigens Class I
• Receptors, Antigen, T-Cell

Topics

• Adult
• Autografts
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cell Line, Tumor
• Female
• Gastrointestinal Neoplasms (genetics, immunology, pathology)
• Histocompatibility Antigens Class I (immunology)
• Humans
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism)
• Male
• Middle Aged
• Neoplasm Metastasis
• Receptors, Antigen, T-Cell (genetics, immunology)
• Transduction, Genetic