Tumor expression of 4-1BB ligand sustains tumor lytic T cells

Hua Zhang, Melinda S. Merchant, Kevin S. Chua, Chand Khanna, Lee J. Helman, Bill Telford, Yvona Ward, Jeffrey Summers, Jeff Toretsky, Elaine K. Thomas, Carl H. June, Crystal L. Mackall

Research output: Contribution to journalArticlepeer-review

Abstract

Inadequate costimulation by solid tumors is generally believed to induce immune tolerance during primary tumor growth. We looked for tumor-specific immunity vs. tolerance in patients with Ewing's sarcoma. Circulating T cells from patients with progressively growing Ewing's tumors displayed MHC restricted tumor-induced proliferation and robust tumor lysis. Tumor-reactive T cells reside within the memory CD3+CD8+ subset and are CD28 -/4-1BB+. Autologous Ewing's tumors expressed 4-1BBL, and tumor-induced T cell proliferation and activation required costimulation by 4-1BBL. Stimulation of PBL with anti-CD3/4-1BBL, but not anti-CD3/anti-CD28 induced tumor lytic effectors. Similarly, in a xenograft model, anti-CD3/4-1BBL expanded T cells controlled primary growth and prevented metastasis of autologous tumors while nonactivated and anti-CD3/anti-CD28 activated CD8+ cells did not. These results question prevailing models of tumor induced tolerance accompanying progressive tumor growth; rather, we show coexistence of progressive tumor growth and anti-tumor immunity, with costimulation provided by the tumor itself. They further demonstrate a potential new therapeutic role for 4-1BBL mediated costimulation in expanding tumor reactive CTLs for use in the adoptive immunotherapy of cancer.

Original languageEnglish (US)
Pages (from-to)579-586
Number of pages8
JournalCancer Biology and Therapy
Volume2
Issue number5
DOIs
StatePublished - Sep 2003

Keywords

  • 4-1BB
  • 4-1BBL
  • Adoptive immunotherapy
  • Ewing's sarcoma
  • T cell co-stimulation

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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