Density of tumour stroma is correlated to outcome after adoptive transfer of CD4+ and CD8+ T cells in a murine mammary carcinoma model

Breast Cancer Res Treat. 2010 Jun;121(3):753-63. doi: 10.1007/s10549-009-0559-y. Epub 2009 Sep 30.

Abstract

Adoptive immunotherapy shows promise for the treatment of cancer; however, partial or mixed responses remain common outcomes due to the heterogeneity of tumours. We studied three murine mammary tumour lines that express an ovalbumin-tagged version of HER-2/neu and reproducibly undergo complete regression (CR), partial regression (PR), or progressive disease (PD) after adoptive transfer of ovalbumin-specific CD8(+) (OT-I) and CD4(+) (OT-II) T cells. The three tumour lines were implanted in immunocompetent C57Bl/6 host mice, and established tumours were treated by adoptive transfer of naive OT-I and OT-II T cells. Tumours of the CR and PR classes triggered almost indistinguishable T cell responses in terms of activation, proliferation, trafficking to the tumour site, infiltration of tumour stroma, and intratumoural T cell proliferation; however, tumours of the PR class showed reduced infiltration of tumour epithelium by donor T cells. PD responses were associated with early impairment of T cell activation and proliferation in draining lymph node, followed by negligible infiltration of tumour tissue by donor T cells. Histopathological determinants of outcome were investigated through an unsupervised analysis of 64 untreated tumours representing the three response classes. Tumours of the CR class had proportionately more stroma, which had a looser, more collagen-rich histological appearance. Thus, the amount and composition of tumour stroma distinguished successfully (CR) from unsuccessful (PR or PD) outcomes after adoptive T cell transfer, a finding that might facilitate the design of immunotherapy trials for human breast cancer.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Epitopes, T-Lymphocyte / immunology*
  • Epitopes, T-Lymphocyte / metabolism
  • Female
  • Immunohistochemistry
  • Immunotherapy, Adoptive / methods*
  • Lymph Nodes / pathology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Stromal Cells / immunology*
  • Stromal Cells / metabolism

Substances

  • Epitopes, T-Lymphocyte