Cancer Immunology, Immunotherapy

, Volume 62, Issue 4, pp 727–736

Modulating the differentiation status of ex vivo-cultured anti-tumor T cells using cytokine cocktails

  • Shicheng Yang
  • Yun Ji
  • Luca Gattinoni
  • Ling Zhang
  • Zhiya Yu
  • Nicholas P. Restifo
  • Steven A. Rosenberg
  • Richard A. Morgan
Original article

DOI: 10.1007/s00262-012-1378-2

Cite this article as:
Yang, S., Ji, Y., Gattinoni, L. et al. Cancer Immunol Immunother (2013) 62: 727. doi:10.1007/s00262-012-1378-2

Abstract

The genetic modification of CD8+ T cells using anti-tumor T-cell receptors (TCR) or chimeric antigen receptors is a promising approach for the adoptive cell therapy of patients with cancer. We previously developed a simplified method for the clinical-scale generation of central memory-like (Tcm) CD8+ T cells following transduction with lentivirus encoding anti-tumor TCR and culture in the presence of IL-2. In this study, we compared different cytokines or combinations of IL-2, IL-7, IL-12, IL-15, and IL-21 to expand genetically engineered CD8+ T cells. We demonstrated that specific cytokine combinations IL-12 plus IL-7 or IL-21 for 3 days followed by withdrawal of IL-12 yielded the phenotype of CD62LhighCD28high CD127highCD27highCCR7high, which is associated with less-differentiated T cells. Genes associated with stem cells (SOX2, NANOG, OCT4, and LIN28A), were also up-regulated by this cytokine cocktail. Moreover, the use of IL-12 plus IL-7 or IL-21 yielded CD8 T cells showing enhanced persistence in the NOD/SCID/γc−/− mouse model. This defined cytokine combination could also alter highly differentiated TIL from melanoma patients into cells with a less-differentiated phenotype. The methodology that we developed for generating a less-differentiated anti-tumor CD8+ T cells ex vivo may be ideal for the adoptive immunotherapy of cancer.

Keywords

CD62LTCR gene therapyT cell receptorCentral memory cellsEffector memory cellsTumor immunity

Supplementary material

262_2012_1378_MOESM1_ESM.eps (3.4 mb)
Supplementary material 1 (EPS 3529 kb)
262_2012_1378_MOESM2_ESM.eps (559 kb)
Supplementary material 2 (EPS 558 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2012

Authors and Affiliations

  • Shicheng Yang
    • 1
    • 2
  • Yun Ji
    • 1
  • Luca Gattinoni
    • 1
  • Ling Zhang
    • 1
  • Zhiya Yu
    • 1
  • Nicholas P. Restifo
    • 1
  • Steven A. Rosenberg
    • 1
  • Richard A. Morgan
    • 1
  1. 1.Surgery Branch, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Department of SurgeryDuke University Medical CenterDurhamUSA