Serial low doses of sorafenib enhance therapeutic efficacy of adoptive T cell therapy in a murine model by improving tumor microenvironment

PLoS One. 2014 Oct 15;9(10):e109992. doi: 10.1371/journal.pone.0109992. eCollection 2014.

Abstract

Requirements of large numbers of transferred T cells and various immunosuppressive factors and cells in the tumor microenvironment limit the applications of adoptive T cells therapy (ACT) in clinic. Accumulating evidences show that chemotherapeutic drugs could act as immune supportive instead of immunosuppressive agents when proper dosage is used, and combined with immunotherapy often results in better treatment outcomes than monotherapy. Controversial immunomodulation effects of sorafenib, a multi-kinases inhibitor, at high and low doses have been reported in several types of cancer. However, what is the range of the low-dose sorafenib will influence the host immunity and responses of ACT is still ambiguous. Here we used a well-established E.G7/OT-1 murine model to understand the effects of serial low doses of sorafenib on both tumor microenvironment and transferred CD8+ T cells and the underlying mechanisms. Sorafenib lowered the expressions of immunosuppressive factors, and enhanced functions and migrations of transferred CD8+ T cells through inhibition of STAT3 and other immunosuppressive factors. CD8+ T cells were transduced with granzyme B promoter for driving imaging reporters to visualize the activation and distribution of transferred CD8+ T cells prior to adoptive transfer. Better activations of CD8+ T cells and tumor inhibitions were found in the combinational group compared with CD8+ T cells or sorafenib alone groups. Not only immunosuppressive factors but myeloid derived suppressive cells (MDSCs) and regulatory T cells (Tregs) were decreased in sorafenib-treated group, indicating that augmentation of tumor inhibition and function of CD8+ T cells by serial low doses of sorafenib were via reversing the immunosuppressive microenvironment. These results revealed that the tumor inhibitions of sorafenib not only through eradicating tumor cells but modifying tumor microenvironment, which helps outcomes of ACT significantly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / immunology
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Drug Administration Schedule
  • Immunosuppressive Agents / administration & dosage*
  • Immunosuppressive Agents / therapeutic use
  • Immunotherapy, Adoptive / methods*
  • Lymphoma / drug therapy
  • Lymphoma / immunology
  • Mice
  • Mice, Transgenic
  • Niacinamide / administration & dosage
  • Niacinamide / analogs & derivatives*
  • Niacinamide / therapeutic use
  • Phenylurea Compounds / administration & dosage*
  • Phenylurea Compounds / therapeutic use
  • Sorafenib
  • Tumor Microenvironment / drug effects*
  • Tumor Microenvironment / immunology

Substances

  • Immunosuppressive Agents
  • Phenylurea Compounds
  • Niacinamide
  • Sorafenib

Grants and funding

This work was supported by the National Science Council, Taiwan. NSC 100-2321-B-010-013, NSC 101-2321-B-010-006 and NSC 102-2321-B-010-005 (JJH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.