Recurrence of intracranial tumors following adoptive T cell therapy can be prevented by direct and indirect killing aided by high levels of tumor antigen cross-presented on stromal cells

Diana L. Thomas, Miri Kim, Natalie A. Bowerman, Samanthi Narayanan, David M. Kranz, Hans Schreiber, Edward J. Roy

Research output: Contribution to journalArticle

Abstract

Elimination of peripheral tumors by adoptively transferred tumor-specific T cells may require killing of cancer cells and tumor stromal cells. Tumor Ags are cross-presented on stromal cells, resulting in direct cytotoxic T cell (CTL) killing of both Ag-expressing cancer cells and stromal cells. Indirect killing of Ag loss variant cells also occurs. We show here that similar processes occur in a brain tumor stromal environment. We used murine cancer cell lines that express high or low levels of a peptide Ag, SIYRYYGL (SIY), recognized by transgenic 2C CD8 + T cells. The two cell lines are killed with equivalent efficiency by 2C T cells in vitro. Following adoptive transfer of 2C T cells into mice with established SIY-Hi or SIY-Lo brain tumors, tumors of both types regressed, but low-Ag-expressing tumors recurred. High-Ag-expressing tumors contained CD11b + cells cross-presenting SIY peptide and were completely eliminated by 2C T cells. To further test the role of cross-presentation, RAG1 -/- H-2 b mice were infused with H-2 k tumor cells expressing high levels of SIY peptide. Adoptively transferred 2C T cells are able to kill cross-presenting H-2 b stromal cells but not H-2 k tumor cells. In peripheral models, this paradigm led to a small static tumor. In the brain, activated 2C T cells were able to kill cross-presenting CD11b + cells and completely eliminate the H-2 k tumors in most mice. Targeting brain tumor stroma or increasing Ag shedding from tumor cells to enhance cross-presentation may improve the clinical success of T cell adoptive therapies.

Original languageEnglish (US)
Pages (from-to)1828-1837
Number of pages10
JournalJournal of Immunology
Volume183
Issue number3
DOIs
StatePublished - Aug 1 2009

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Neoplasm Antigens
Stromal Cells
Cell- and Tissue-Based Therapy
T-Lymphocytes
Recurrence
Neoplasms
Brain Neoplasms
Cross-Priming
Peptides
Cell Line
Adoptive Transfer

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Recurrence of intracranial tumors following adoptive T cell therapy can be prevented by direct and indirect killing aided by high levels of tumor antigen cross-presented on stromal cells. / Thomas, Diana L.; Kim, Miri; Bowerman, Natalie A.; Narayanan, Samanthi; Kranz, David M.; Schreiber, Hans; Roy, Edward J.

In: Journal of Immunology, Vol. 183, No. 3, 01.08.2009, p. 1828-1837.

Research output: Contribution to journalArticle

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