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

• Published in: The Journal of immunology (1950) 2009-08, Vol.183 (3), p.1828-1837
• Main Authors: Thomas, Diana L, Kim, Miri, Bowerman, Natalie A, Narayanan, Samanthi, Kranz, David M, Schreiber, Hans, Roy, Edward J
• Format: Article
• Language: English
• Subjects: Adoptive Transfer - methods; Animals; Antigens, Neoplasm - immunology; Brain Neoplasms - pathology; Brain Neoplasms - prevention & control; Brain Neoplasms - therapy; Cell Line, Tumor; Cross-Priming - immunology; Cytotoxicity, Immunologic; Mice; Mice, Knockout; Secondary Prevention; Stromal Cells - immunology; Stromal Cells - pathology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - transplantation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0802322

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.