Breast Cancer Research and Treatment

, Volume 142, Issue 1, pp 45–57

Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells

  • Kyle K. Payne
  • Christine K. Zoon
  • Wen Wan
  • Khin Marlar
  • Rebecca C. Keim
  • Mehrab Nasiri Kenari
  • A. Latif Kazim
  • Harry D. Bear
  • Masoud H. Manjili
Preclinical Study

DOI: 10.1007/s10549-013-2733-5

Cite this article as:
Payne, K.K., Zoon, C.K., Wan, W. et al. Breast Cancer Res Treat (2013) 142: 45. doi:10.1007/s10549-013-2733-5

Abstract

Two major barriers in the immunotherapy of breast cancer include tumor-induced immune suppression and the establishment of long-lasting immune responses against the tumor. Recently, we demonstrated in an animal model of breast carcinoma that expanding and reprogramming tumor-sensitized lymphocytes, ex vivo, yielded T memory (Tm) cells as well as activated CD25+ NKT cells and NK cells. The presence of activated CD25+ NKT and NK cells rendered reprogrammed T cells resistant to MDSC-mediated suppression, and adoptive cellular therapy (ACT) of reprogrammed lymphocytes protected the host from tumor development and relapse. Here, we performed a pilot study to determine the clinical applicability of our protocol using peripheral blood mononuclear cells (PBMCs) of breast cancer patients, ex vivo. We show that bryostatin 1 and ionomycin combined with IL-2, IL-7, and IL-15 can expand and reprogram tumor-sensitized PBMCs. Reprogrammed lymphocytes contained activated CD25+ NKT and NK cells as well as Tm cells and displayed enhanced reactivity against HER-2/neu in the presence of MDSCs. The presence of activated NKT cells was highly correlated with the rescue of anti-HER-2/neu immune responses from MDSC suppression. Ex vivo blockade experiments suggest that the NKG2D pathway may play an important role in overcoming MDSC suppression. Our results show the feasibility of reprogramming tumor-sensitized immune cells, ex vivo, and provide rationale for ACT of breast cancer patients.

Keywords

Cancer immunotherapy Breast cancer NKT cells NK cells Myeloid-derived suppressor cells (MDSCs) 

Abbreviations

ACT

Adoptive cellular therapy

B/I

Bryostatin and ionomycin

DC

Dendritic cell

ICD

Intracellular domain

MDSC

Myeloid-derived suppressor cell

PBMC

Peripheral blood mononuclear cell

PCC

Pearson correlation coefficient

Tcm

T central memory cells

TcR

T cell receptor

Te

T effector cells

Tm

T memory cells

Variable beta

γ-c

Gamma chain

Supplementary material

10549_2013_2733_MOESM1_ESM.ppt (703 kb)
Supplementary material 1 (PPT 701 kb)

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Kyle K. Payne
    • 1
  • Christine K. Zoon
    • 2
  • Wen Wan
    • 3
  • Khin Marlar
    • 5
  • Rebecca C. Keim
    • 1
  • Mehrab Nasiri Kenari
    • 4
  • A. Latif Kazim
    • 5
  • Harry D. Bear
    • 2
  • Masoud H. Manjili
    • 1
  1. 1.Department of Microbiology and ImmunologyVirginia Commonwealth University, Massey Cancer CenterRichmondUSA
  2. 2.Division of Surgical Oncology, Department of SurgeryVirginia Commonwealth University, Massey Cancer CenterRichmondUSA
  3. 3.Department of BiostatisticsVirginia Commonwealth University, Massey Cancer CenterRichmondUSA
  4. 4.Department of Molecular and Cellular BiologyRoswell Park Cancer InstituteBuffaloUSA
  5. 5.Department of Cell Stress BiologyRoswell Park Cancer InstituteBuffaloUSA

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