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.
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.
Thomas
Diana L
DL
University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA.
Kim
Miri
M
Bowerman
Natalie A
NA
Narayanan
Samanthi
S
Kranz
David M
DM
Schreiber
Hans
H
Roy
Edward J
EJ
D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001932:Brain Neoplasms / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D045744:Cell Line, Tumor; D045142:Cross-Priming / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D051379:Mice; D018345:Mice, Knockout; D055502:Secondary Prevention; D017154:Stromal Cells / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation*
D000951:Antigens, Neoplasm