Cancer Immunology, Immunotherapy

, Volume 59, Issue 8, pp 1173–1183

RNA interference targeting programmed death receptor-1 improves immune functions of tumor-specific T cells

  • Lisa Borkner
  • Andrew Kaiser
  • Willeke van de Kasteele
  • Reinhard Andreesen
  • Andreas Mackensen
  • John B. Haanen
  • Ton N. Schumacher
  • Christian Blank
Original Article

DOI: 10.1007/s00262-010-0842-0

Cite this article as:
Borkner, L., Kaiser, A., van de Kasteele, W. et al. Cancer Immunol Immunother (2010) 59: 1173. doi:10.1007/s00262-010-0842-0

Abstract

Adoptive cell transfer (ACT), either using rapidly expanded tumor infiltrating lymphocytes or T-cell receptor transduced peripheral blood lymphocytes, can be considered one of the most promising approaches in cancer immunotherapy. ACT results in the repopulation of the host with high frequencies of tumor-specific T cells; however, optimal function of these cells within the tumor micro-environment is required to reach long-term tumor clearance. We and others have shown that ongoing anti-tumor immune responses can be impaired by the expression of ligands, such as PD-L1 (B7-H1) on tumor cells. Such inhibitory molecules can affect T cells at the effector phase via their receptor PD-1. PD-L1/PD-1 interaction has indeed been shown crucial in inducing T-cell anergy and maintaining peripheral tolerance. In order to maximize anti-tumor responses, antibodies that target the PD-1/PD-L1 axis are currently in phase I/II trials. Alternatively, a more refined approach could be the selective targeting of PD-1 in tumor-specific T cells to obtain long-term resistance against PD-1-mediated inhibition. We addressed whether this goal could be achieved by means of retroviral siRNA delivery. Effective siRNA sequences resulting in the reduction of surface PD-1 expression led to improved murine as well as human T-cell immune functions in response to PD-L1 expressing melanoma cells. These data suggest that blockade of PD-1-mediated T-cell inhibition through siRNA forms a promising approach to achieve long-lasting enhancement of tumor-specific T-cell function in adoptive T-cell therapy protocols.

Keywords

siRNAT cellPD-1PD-L1B7-H1

Abbreviations

MFI

Mean fluorescence intensity

PD-1

Programmed death-1 receptor (CD279)

PD-L1

Programmed death ligand-1 (B7-H1, CD274)

PBL

Peripheral blood leukocytes

TIL

Tumor infiltrating lymphocytes

TCR

T cell receptor

mAb

Monoclonal antibody

Supplementary material

262_2010_842_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1136 kb)

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Lisa Borkner
    • 1
    • 2
  • Andrew Kaiser
    • 1
  • Willeke van de Kasteele
    • 1
  • Reinhard Andreesen
    • 2
  • Andreas Mackensen
    • 3
  • John B. Haanen
    • 4
  • Ton N. Schumacher
    • 1
  • Christian Blank
    • 4
  1. 1.Division of ImmunologyThe Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL)AmsterdamThe Netherlands
  2. 2.Department of Hematology and OncologyUniversitätsklinikum RegensburgRegensburgGermany
  3. 3.Department of Hematology and OncologyUniversitätsklinikum ErlangenErlangenGermany
  4. 4.Department of Medical Oncology and Division of ImmunologyThe Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL)AmsterdamThe Netherlands