Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model.
To study the immune response to prostate cancer, we developed an autochthonous animal model based on the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse in which spontaneously developing tumors express influenza hemagglutinin as a unique, tumor-associated antigen. Our prior studies in these animals showed immunologic tolerance to hemagglutinin, mirroring the clinical situation in patients with cancer who are generally nonresponsive to their disease. We used this physiologically relevant animal model to assess the immunomodulatory effects of cyclophosphamide when administered in combination with an allogeneic, cell-based granulocyte-macrophage colony-stimulating factor-secreting cancer immunotherapy. Through adoptive transfer of prostate/prostate cancer-specific CD8 T cells as well as through studies of the endogenous T-cell repertoire, we found that cyclophosphamide induced a marked augmentation of the antitumor immune response. This effect was strongly dependent on both the dose and the timing of cyclophosphamide administration. Mechanistic studies showed that immune augmentation by cyclophosphamide was associated with a transient depletion of regulatory T cells in the tumor draining lymph nodes but not in the peripheral circulation. Interestingly, we also noted effects on dendritic cell phenotype; low-dose cyclophosphamide was associated with increased expression of dendritic cell maturation markers. Taken together, these data clarify the dose, timing, and mechanism of action by which immunomodulatory cyclophosphamide can be translated to a clinical setting in a combinatorial cancer treatment strategy.
Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Satoshi
S
Wada
Kiyoshi
K
Yoshimura
Edward L
EL
Hipkiss
Tim J
TJ
Harris
Hung-Rong
HR
Yen
Monica V
MV
Goldberg
Joseph F
JF
Grosso
Derese
D
Getnet
Angelo M
AM
Demarzo
George J
GJ
Netto
Robert
R
Anders
Drew M
DM
Pardoll
Charles G
CG
Drake
D019264:Adoptive Transfer; D000818:Animals; D016827:CD8 Antigens / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003520:Cyclophosphamide / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D006388:Hemagglutinins / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D016827:CD8 Antigens; D006388:Hemagglutinins; D003520:Cyclophosphamide