Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo

Cancer Immunol Immunother. 2013 Feb;62(2):383-91. doi: 10.1007/s00262-012-1343-0. Epub 2012 Aug 25.

Abstract

Several chemotherapeutic drugs have immune-modulating effects. For example, cyclophosphamide (CP) and gemcitabine (GEM) diminish immunosuppression by regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), respectively. Here, we show that intermittent (metronomic) chemotherapy with low-dose CP plus GEM can induce anti-tumor T cell immunity in CT26 colon carcinoma-bearing mice. Although no significant growth suppression was observed by injections of CP (100 mg/kg) at 8-day intervals or those of CP (50 mg/kg) at 4-day intervals, CP injection (100 mg/kg) increased the frequency of tumor peptide-specific T lymphocytes in draining lymph nodes, which was abolished by two injections of CP (50 mg/kg) at a 4-day interval. Alternatively, injection of GEM (50 mg/kg) was superior to that of GEM (100 mg/kg) in suppressing tumor growth in vivo, despite the smaller dose. When CT26-bearing mice were treated with low-dose (50 mg/kg) CP plus (50 mg/kg) GEM at 8-day intervals, tumor growth was suppressed without impairing T cell function; the effect was mainly T cell dependent. The metronomic combination chemotherapy cured one-third of CT26-bearing mice that acquired tumor-specific T cell immunity. The combination therapy decreased Foxp3 and arginase-1 mRNA levels but increased IFN-γ mRNA expression in tumor tissues. The percentages of tumor-infiltrating CD45(+) cells, especially Gr-1(high) CD11b(+) MDSCs, were decreased. These results indicate that metronomic chemotherapy with low-dose CP plus GEM is a promising protocol to mitigate totally Treg- and MDSC-mediated immunosuppression and elicit anti-tumor T cell immunity in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Metronomic*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Arginase / biosynthesis
  • CD11b Antigen / analysis
  • Cell Line, Tumor
  • Cyclophosphamide / administration & dosage*
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Female
  • Forkhead Transcription Factors / biosynthesis
  • Interferon-gamma / biosynthesis
  • Leukocyte Common Antigens / analysis
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms / drug therapy*
  • Receptors, Chemokine / analysis
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • Tumor Escape / drug effects
  • Tumor Escape / immunology

Substances

  • CD11b Antigen
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Gr-1 protein, mouse
  • Receptors, Chemokine
  • Deoxycytidine
  • Interferon-gamma
  • Cyclophosphamide
  • gemcitabine
  • Leukocyte Common Antigens
  • Ptprc protein, mouse
  • Arg1 protein, mouse
  • Arginase