Rapid accumulation of adoptively transferred CD8+ T cells at the tumor site is associated with long-term control of SV40 T antigen-induced tumors.
We previously established a model to study CD8(+) T cell (T(CD8))-based adoptive immunotherapy of cancer using line SV11 mice that develop choroid plexus tumors in the brain due to transgenic expression of Simian Virus 40 large T antigen (Tag). These mice are tolerant to the three dominant T(CD8)-recognized Tag epitopes I, II/III and IV. However, adoptive transfer of spleen cells from naïve C57BL/6 (B6) mice prolongs SV11 survival following T(CD8) priming against the endogenous Tag epitope IV. In addition, survival of SV11 mice is dramatically increased following transfer of lymphocytes from Tag-immune B6 mice. In the current study, we compared the kinetics and magnitude of Tag-specific T(CD8) accumulation at the tumor site following adoptive transfer with a high dose of either Tag-immune or naïve donor cells or decreasing doses of Tag-immune lymphocytes. Following adoptive transfer of Tag-immune cells, epitope I- and IV-specific T(CD8) accumulated to high levels in the brain of SV11 mice, peaking at 5-7 days, while epitope IV-specific T(CD8 )derived from naïve donors required three weeks to achieve peak levels. A similar delay in the peak of epitope IV-specific T(CD8) accumulation was observed when tenfold fewer Tag-immune donor cells were administered, reducing control of tumor progression. These results suggest that efficient and prolonged control of established autochthonous tumors is associated with high-level early accumulation of adoptively transferred T cells. We also provide evidence that although multiple specificities are represented in the Tag immune donor lymphocytes, epitope IV-specific donor T(CD8) play a predominant role in control of tumor growth.
Yorty
Jodi L
JL
Department of Microbiology and Immunology, H107, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Tevethia
Satvir S
SS
Schell
Todd D
TD
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D005434:Flow Cytometry / Q000379:methods; D007107:Immune System; D007167:Immunotherapy / Q000379:methods*; D007700:Kinetics; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry
D000952:Antigens, Polyomavirus Transforming; D016207:Cytokines; D000939:Epitopes; D010455:Peptides