Rapid accumulation of adoptively transferred CD8+ T cells at the tumor site is associated with long-term control of SV40 T antigen-induced tumors

Cancer Immunol Immunother. 2008 Jun;57(6):883-95. doi: 10.1007/s00262-007-0424-y. Epub 2007 Nov 15.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Polyomavirus Transforming / metabolism*
  • Brain / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cytokines / metabolism
  • Epitopes / chemistry
  • Flow Cytometry / methods
  • Immune System
  • Immunotherapy / methods*
  • Kinetics
  • Lymphocytes / immunology
  • Lymphocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / immunology
  • Neoplasms / metabolism*
  • Peptides / chemistry

Substances

  • Antigens, Polyomavirus Transforming
  • Cytokines
  • Epitopes
  • Peptides