Cyclophosphamide induces dynamic alterations in the host microenvironments resulting in a Flt3 ligand-dependent expansion of dendritic cells.
Preconditioning a recipient host with lymphodepletion can markedly augment adoptive T cell therapy. However, the precise mechanisms involved are poorly understood. In a recent study, we observed a significant increase in the circulating levels of dendritic cells (DCs; CD11c(+)CD11b(+)) during the recovery from cyclophosphamide (CTX)-induced lymphodepletion. Herein, we demonstrate that the CTX-induced DC expansion was not altered by adjuvant chemotherapy or tumor burden but was augmented by coadministration of granulocyte-colony stimulating factor. Although the increase in the number of DCs was preceded by a systemic expansion of a population expressing the phenotype of myeloid-derived suppressor cells (Gr-1(+)CD11b(+)), depletion of these Gr-1(+) cells had no effect on the noted expansion. Moreover, when Gr-1(high)CD11b(high) cells were sorted from CTX-treated mice and adoptively transferred into control or CTX-treated recipients, they did not differentiate into DCs. Post-CTX expansion of DCs was associated with proliferation of DCs in bone marrow (BM) during the lymphopenic phase and in the blood and spleen during the recovery phase. Furthermore, adoptive transfer of BM cells from CTX-treated mice produced equal numbers of DCs in the blood of either CTX-treated or untreated recipients. CTX induced a dynamic surge in the expression of growth factors and chemokines in BM, where CCR2 and Flt3 signaling pathways were critical for DC expansion. In sum, our data suggest that CTX induces proliferation of DCs in BM prior to their expansion in the periphery. Targeting DCs at these phases would significantly improve their contribution to the clinical application of lymphodepletion to adoptive immunotherapy.
Salem
Mohamed L
ML
Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. salemm@musc.edu
Al-Khami
Amir A
AA
El-Naggar
Sabry A
SA
Díaz-Montero
C Marcela
CM
Chen
Yian
Y
Cole
David J
DJ
D019264:Adoptive Transfer; D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology*; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D007970:Leukopenia / Q000276:immunology / Q000473:pathology; D008024:Ligands; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D019707:Receptors, Chemokine / Q000096:biosynthesis
D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D008024:Ligands; D008565:Membrane Proteins; D019707:Receptors, Chemokine; C084881:flt3 ligand protein; D003520:Cyclophosphamide