Breast Cancer Research and Treatment

, Volume 126, Issue 2, pp 385–394

CD4+ T cells inhibit the neu-specific CD8+ T-cell exhaustion during the priming phase of immune responses against breast cancer

Authors

  • Maciej Kmieciak
    • Department of Microbiology & ImmunologyVirginia Commonwealth University Massey Cancer Center
  • Andrea Worschech
    • Infectious Disease and Immunogenetics Section (IDIS), Department on Transfusion Medicine and Center for Human ImmunologyNational Institutes of Health
    • Institute for BiochemistryUniversity of Wuerzburg
    • Genelux Corp., Research and Development
  • Hooman Nikizad
    • Department of Microbiology & ImmunologyVirginia Commonwealth University Massey Cancer Center
  • Madhu Gowda
    • Department of PediatricsVirginia Commonwealth University Massey Cancer Center
  • Mehran Habibi
    • Johns Hopkins UniversitySchool of Medicine
  • Amy Depcrynski
    • Department of PathologyVirginia Commonwealth University Massey Cancer Center
  • Ena Wang
    • Infectious Disease and Immunogenetics Section (IDIS), Department on Transfusion Medicine and Center for Human ImmunologyNational Institutes of Health
  • Kamar Godder
    • Department of PediatricsVirginia Commonwealth University Massey Cancer Center
  • Shawn E. Holt
    • Department of PathologyVirginia Commonwealth University Massey Cancer Center
  • Francesco M. Marincola
    • Infectious Disease and Immunogenetics Section (IDIS), Department on Transfusion Medicine and Center for Human ImmunologyNational Institutes of Health
    • Department of Microbiology & ImmunologyVirginia Commonwealth University Massey Cancer Center
Preclinical study

DOI: 10.1007/s10549-010-0942-8

Cite this article as:
Kmieciak, M., Worschech, A., Nikizad, H. et al. Breast Cancer Res Treat (2011) 126: 385. doi:10.1007/s10549-010-0942-8

Abstract

Studies conducted in animal model of infectious diseases or H-Y antigen model suggest a crucial role for CD4+ T cells in providing help for CD8+ T-cell memory responses. This concept suggests that inclusion of T helper epitopes in vaccine formulation will result in improved CD8+ T-cell responses. Although this concept has been applied to cancer vaccine design, the role of CD4+ T cells in the memory differentiation of CD8+ T cells and retention of their anti-tumor function have never been tested in breast cancer model. Using the FVB mouse model of neu-positive breast carcinoma we report for the first time that helpless T cells showed cytostatic or tumor inhibitory effects during primary tumor challenge whereas, helped T cells showed cytotoxic effects and resulted in complete tumor rejection. Such differential effects, in vivo, were associated with higher frequency of CD8+PD-L1+ and CD8+PD-1+ T cells in animals harboring helpless T cells as well as higher titer of IL-2 in the sera of animals harboring helped T cells. However, depletion of CD4+ T cells did not alter the ability of neu-specific CD8+ T cells to differentiate into memory cells and to retain their effector function against the tumor during recall challenge. These results suggest the inhibitory role of CD4+ T cells on CD8+ T-cell exhaustion without substantial effects on the differentiation of memory T cells during priming phase of the immune responses against breast cancer.

Keywords

Breast cancerHER-2/neuHelpless CD8+ T cellsCD4+ helper T cellsMemory T cells

Supplementary material

10549_2010_942_MOESM1_ESM.tif (2.4 mb)
Fig. S1FVB mice (n = 3) were depleted of CD4+ and CD8+ T cells by i.p. injection of GK1.5 and 2.43 Abs, respectively. Animals were then inoculated with MMC (5 × 106 cells/mouse) and tumor growth was determined. (TIFF 2457 kb)

Copyright information

© Springer Science+Business Media, LLC. 2010