Immunomodulatory effects of sorafenib on peripheral immune effector cells in metastatic renal cell carcinoma

Eur J Cancer. 2011 Mar;47(5):690-6. doi: 10.1016/j.ejca.2010.11.021. Epub 2011 Jan 5.

Abstract

Background: Tyrosine kinase inhibitors (TKI) such as sorafenib have substantially improved the prognosis of metastatic renal cell carcinoma (mRCC) patients, but long-term remissions have only been reached with immunotherapy. Sequencing or combining TKI treatment with immunotherapy may represent an attractive therapeutic concept. However, in vitro data have shown that TKI may not only affect tumour cells, but also inhibit signalling in immune effector cells. Therefore, we asked whether sorafenib had an influence on peripheral immune effector cells in a cohort of 35 mRCC patients receiving sorafenib treatment.

Methods: Peripheral blood (pB) samples were analysed at baseline and after 8 weeks of treatment. IL-10 and TGF-ß mRNA levels were quantified by RT-PCR; regulatory T cell (Treg) counts and intracellular cytokine responses (TNF-α, IFN-γ, IL-10 and TGF-ß) of mononuclear cell subsets were determined by flow cytometry after in vitro stimulation with PMA/ionomycin.

Results: Sorafenib did not alter the elevated TGF-ß and IL-10 mRNA levels or elevated frequencies of IL-10 and TGF-ß producing monocytes and had no influence on type 1 cytokine responses in pB. CD4+CD25(high) FOXP3+/CD3+ T cells, likely representing Treg cells, decreased during sorafenib therapy.

Conclusions: In vivo, sorafenib treatment was associated with a decrease in frequency of Treg cells without influencing the function of peripheral immune effector cells. Therefore, although sorafenib did not convert the immunosuppressive phenotype associated with mRCC, it seemed to be a possible candidate for combination with immunotherapy.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / immunology*
  • Antineoplastic Agents / therapeutic use
  • Benzenesulfonates / immunology*
  • Benzenesulfonates / therapeutic use
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / immunology
  • Cytokines / biosynthesis
  • Female
  • Humans
  • Immunologic Factors / immunology*
  • Immunologic Factors / therapeutic use
  • Interleukin-10 / metabolism
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / immunology
  • Leukocytes, Mononuclear / immunology
  • Male
  • Middle Aged
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Pyridines / immunology*
  • Pyridines / therapeutic use
  • RNA, Messenger / metabolism
  • Sorafenib
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Antineoplastic Agents
  • Benzenesulfonates
  • Cytokines
  • Immunologic Factors
  • Phenylurea Compounds
  • Pyridines
  • RNA, Messenger
  • Transforming Growth Factor beta1
  • Interleukin-10
  • Niacinamide
  • Sorafenib