Signatures associated with rejection or recurrence in HER-2/neu-positive mammary tumors

Andrea Worschech, Maciej Kmieciak, Keith L. Knutson, Harry D. Bear, Aladar A. Szalay, Ena Wang, Francesco M. Marincola, Masoud H. Manjili

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

We have previously shown T-cell-mediated rejection of the neu-overexpressing mammary carcinoma cells (MMC) in wild-type FVB mice. However, following rejection of primary tumors, a fraction of animals experienced a recurrence of a neu antigen-negative variant (ANV) of MMC (tumor evasion model) after a long latency period. In the present study, we determined that T cells derived from wild-type FVB mice can specifically recognize MMC by secreting IFN-γ and can induce apoptosis of MMC in vitro. Neu transgenic (FVBN202) mice develop spontaneous tumors and cannot reject it (tumor tolerance model). To dissect the mechanisms associated with rejection or tolerance of MMC tumors, we compared transcriptional patterns within the tumor microenvironment of MMC undergoing rejection with those that resisted it either because of tumor evasion/antigen loss recurrence (ANV tumors) or because of intrinsic tolerance mechanisms displayed by the transgenic mice. Gene profiling confirmed that immune rejection is primarily mediated through activation of IFN-stimulated genes and T-cell effector mechanisms. The tumor evasion model showed combined activation of Th1 and Th2 with a deviation toward Th2 and humoral immune responses that failed to achieve rejection likely because of lack of target antigen. Interestingly, the tumor tolerance model instead displayed immune suppression pathways through activation of regulatory mechanisms that included in particular the overexpression of interleukin-10 (IL-10), IL-10 receptor, and suppressor of cytokine signaling (SOCS)-1 and SOCS-3. These data provide a road map for the identification of novel biomarkers of immune responsiveness in clinical trials.

Original languageEnglish (US)
Pages (from-to)2436-2446
Number of pages11
JournalCancer research
Volume68
Issue number7
DOIs
StatePublished - Apr 1 2008

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Worschech, A., Kmieciak, M., Knutson, K. L., Bear, H. D., Szalay, A. A., Wang, E., Marincola, F. M., & Manjili, M. H. (2008). Signatures associated with rejection or recurrence in HER-2/neu-positive mammary tumors. Cancer research, 68(7), 2436-2446. https://doi.org/10.1158/0008-5472.CAN-07-6822