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

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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-1high 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.

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Acknowledgments

We thank Ms. Tamami Moritani for her technical assistance. This study was supported in part by grants from the Ministry of Education, Science, Sport, Culture, and Technology of Japan (no. 24501331 to M. H. and no. 23701074 to N. H.) and from the Shimane University Medical Education and Research Foundation.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Experimental Animals, Center for Integrated Research in Science, Shimane University, Izumo, Shimane, Japan

    Miki Tongu & Takaya Yamada

  2. Department of Immunology, Faculty of Medicine, Shimane University, Izumo, Shimane, 693-8501, Japan

    Nanae Harashima, Hiroyuki Monma & Mamoru Harada

  3. Department of Surgery, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan

    Hiroyuki Monma & Touko Inao

  4. Department of Otorhinolaryngology, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan

    Hideyuki Kawauchi

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  1. Miki Tongu
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  2. Nanae Harashima
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Correspondence to Mamoru Harada.

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Tongu, M., Harashima, N., Monma, H. et al. Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo. Cancer Immunol Immunother 62, 383–391 (2013). https://doi.org/10.1007/s00262-012-1343-0

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  • DOI: https://doi.org/10.1007/s00262-012-1343-0

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