Adoptive cytotoxic T lymphocyte therapy triggers a counter-regulatory immunosuppressive mechanism via recruitment of myeloid-derived suppressor cells

Int J Cancer. 2014 Apr 15;134(8):1810-22. doi: 10.1002/ijc.28506. Epub 2013 Oct 21.


Complex interactions among multiple cell types contribute to the immunosuppressive milieu of the tumor microenvironment. Using a murine model of adoptive T-cell immunotherapy (ACT) for B16 melanoma, we investigated the impact of tumor infiltrating cells on this complex regulatory network in the tumor. Transgenic pmel-1-specific cytotoxic T lymphocytes (CTLs) were injected intravenously into tumor-bearing mice and could be detected in the tumor as early as on day 1, peaking on day 3. They produced IFN-γ, exerted anti-tumor activity and inhibited tumor growth. However, CTL infiltration into the tumor was accompanied by the accumulation of large numbers of cells, the majority of which were CD11b(+) Gr1(+) myeloid-derived suppressor cells (MDSCs). Notably, CD11b(+) Gr1(int) Ly6G(-) Ly6C(+) monocytic MDSCs outnumbered the CTLs by day 5. They produced nitric oxide, arginase I and reactive oxygen species, and inhibited the proliferation of antigen-specific CD8(+) T cells. The anti-tumor activity of the adoptively-transferred CTLs and the accumulation of MDSCs both depended on IFN-γ production on recognition of tumor antigens by the former. In CCR2(-/-) mice, monocytic MDSCs did not accumulate in the tumor, and inhibition of tumor growth by ACT was improved. Thus, ACT triggered counter-regulatory immunosuppressive mechanism via recruitment of MDSCs. Our results suggest that strategies to regulate the treatment-induced recruitment of these MDSCs would improve the efficacy of immunotherapy.

Keywords: CTL; MDSC; adoptive transfer; immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginase / biosynthesis
  • CD11b Antigen / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Immunosuppression Therapy
  • Immunotherapy, Adoptive / methods*
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / metabolism*
  • Male
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Neoplastic Stem Cells / immunology*
  • Nitric Oxide / biosynthesis
  • Reactive Oxygen Species / metabolism
  • Receptors, CCR2 / deficiency
  • Receptors, CCR2 / genetics
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism
  • Tumor Microenvironment


  • CD11b Antigen
  • Ccr2 protein, mouse
  • Reactive Oxygen Species
  • Receptors, CCR2
  • Nitric Oxide
  • Interferon-gamma
  • Arg1 protein, mouse
  • Arginase