A Nonimmunogenic Sarcoma Transduced with the cDNA for Interferon γ Elicits CD8+ T Cells against the Wild-type Tumor: Correlation with Antigen Presentation Capability

Nicholas P. Restifo, Paul J. Spiess, Stephen E. Karp, James J. Mulé, Steven A. Kosenberg

Research output: Contribution to journalArticle

Abstract

To be recognized by CD8+ T lymphocytes, target cells must process and present peptide antigens in the context of major histocompatibility complex (MHC) class I molecule The nonimmunogenic, low class I-expressing, methylcholanthrene (MCA)-induced routine sarcoma cell line, MCA 101, is a poor presenter of endogenously generated viral antigens to specific CD8+ T lymphocytes and cannot be used to generate tumor infiltrating lymphocytes (TIL). Since interferon γ (IFN-γ) has been shown to upregulate three sets of molecules important for antigen processing and presentation, we retrovirally transduced wild-type MCA 101 (101.WT) tumor with the mIFN-γ cDNA to create the 101.NAT cell line. Unlike 101.WT, some clones of retrovirally transduced 101.NAT tumor expressed high levels of class I, and could be used to generate CD8+ TIL. More importantly, these TIL were therapeutic in vivo against established pulmonary metastases from the wild-type tumor. Although not uniformly cytotoxic amongst several separate cultures, these TIL did specifically release cytokines (IFN-γ, and tumor necrosis factor-α) in response to 101.WT targets. 101.WT's antigen'presentation ddidt was also reversed by gene modification with mIFN-γ, cDNA. 101.NAT had a greatly improved capacity to present viral antigens to CD8+ cytotoxic T lymphocytes. These findings show that a nonimmunogenic tumor, incapable of generating a CD8+ T cell immune response, could be gene-modified to generate a therapeutically useful immune response against the wild-type tumor. This strategy may be useful in developing treatments for tumor histologies not thought to be susceptible to T cell-based immunotherapy.

Original languageEnglish (US)
Pages (from-to)1423-1431
Number of pages9
JournalJournal of Experimental Medicine
Volume175
Issue number6
DOIs
StatePublished - Jun 1 1992

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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