Cancer Immunology, Immunotherapy

, Volume 59, Issue 1, pp 137–148 | Cite as

Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination

  • Vedran Radojcic
  • Karl B. Bezak
  • Mario Skarica
  • Maria A. Pletneva
  • Kiyoshi Yoshimura
  • Richard D. Schulick
  • Leo Luznik
Original Article

Abstract

Using a model of established malignancy, we found that cyclophosphamide (Cy), administered at a dose not requiring hematopoietic stem cell support, is superior to low-dose total body irradiation in augmenting antitumor immunity. We observed that Cy administration resulted in expansion of tumor antigen-specific T cells and transient depletion of CD4+Foxp3+ regulatory T cells (Tregs). The antitumor efficacy of Cy was not improved by administration of anti-CD25 monoclonal antibody given to induce more profound Treg depletion. We found that Cy, through its myelosuppressive action, induced rebound myelopoiesis and perturbed dendritic cell (DC) homeostasis. The resulting DC turnover led to the emergence of tumor-infiltrating DCs that secreted more IL-12 and less IL-10 compared to those from untreated tumor-bearing animals. These newly recruited DCs, originating from proliferating early DC progenitors, were fully capable of priming T cell responses and ineffective in inducing expansion of Tregs. Together, our results show that Cy-mediated antitumor effects extend beyond the well-documented cytotoxicity and lymphodepletion and include resetting the DC homeostasis, thus providing an excellent platform for integration with other immunotherapeutic strategies.

Keywords

Nonmyeloablative chemotherapy Dendritic cells Hematopoietic stem cells Antitumor immunity 

Supplementary material

262_2009_734_MOESM1_ESM.pdf (420 kb)
Supplementary figures (PDF 420 kb)

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Vedran Radojcic
    • 1
  • Karl B. Bezak
    • 1
  • Mario Skarica
    • 1
  • Maria A. Pletneva
    • 1
  • Kiyoshi Yoshimura
    • 1
    • 2
  • Richard D. Schulick
    • 1
    • 2
  • Leo Luznik
    • 1
    • 3
  1. 1.Department of OncologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of SurgeryJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.BaltimoreUSA

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