Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination.
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.
Radojcic
Vedran
V
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Bezak
Karl B
KB
Skarica
Mario
M
Pletneva
Maria A
MA
Yoshimura
Kiyoshi
K
Schulick
Richard D
RD
Luznik
Leo
L
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000494:pharmacology* / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006706:Homeostasis; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D014916:Whole-Body Irradiation
D000970:Antineoplastic Agents; D007155:Immunologic Factors; D003520:Cyclophosphamide