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

  • Maciej Kmieciak
  • Andrea Worschech
  • Hooman Nikizad
  • Madhu Gowda
  • Mehran Habibi
  • Amy Depcrynski
  • Ena Wang
  • Kamar Godder
  • Shawn E. Holt
  • Francesco M. Marincola
  • Masoud H. Manjili
Preclinical study


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.


Breast cancer HER-2/neu Helpless CD8+ T cells CD4+ helper T cells Memory 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)


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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Maciej Kmieciak
    • 1
  • Andrea Worschech
    • 2
    • 3
    • 4
  • Hooman Nikizad
    • 1
  • Madhu Gowda
    • 5
  • Mehran Habibi
    • 6
  • Amy Depcrynski
    • 7
  • Ena Wang
    • 2
  • Kamar Godder
    • 5
  • Shawn E. Holt
    • 7
  • Francesco M. Marincola
    • 2
  • Masoud H. Manjili
    • 1
  1. 1.Department of Microbiology & ImmunologyVirginia Commonwealth University Massey Cancer CenterRichmondUSA
  2. 2.Infectious Disease and Immunogenetics Section (IDIS), Department on Transfusion Medicine and Center for Human ImmunologyNational Institutes of HealthBethesdaUSA
  3. 3.Institute for BiochemistryUniversity of WuerzburgWuerzburgGermany
  4. 4.Genelux Corp., Research and DevelopmentSan DiegoUSA
  5. 5.Department of PediatricsVirginia Commonwealth University Massey Cancer CenterRichmondUSA
  6. 6.Johns Hopkins UniversitySchool of MedicineBaltimoreUSA
  7. 7.Department of PathologyVirginia Commonwealth University Massey Cancer CenterRichmondUSA

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