Recovery from cyclophosphamide-induced lymphopenia results in expansion of immature dendritic cells which can mediate enhanced prime-boost vaccination antitumor responses in vivo when stimulated with the TLR3 agonist poly(I:C).
Recent preclinical studies suggest that vaccination following adoptive transfer of CD8(+) T cells into a lymphopenic host can augment the therapeutic antitumor responses of the transferred cells. However, the mechanism by which the lymphopenic microenvironment benefits Ag-specific CD8(+) T cell responses remains elusive. We show herein that induction of lymphodepletion by a single 4 mg cyclophosphamide (CTX) treatment induces a marked expansion of immature dendritic cells (DCs) in the peripheral blood on days 8-16 post-CTX (termed restoration phase). In vitro, these DCs were functional, because they showed normal phagocytosis and effective Ag presentation capability upon activation. In vivo, administration of the TLR3 agonist poly(I:C) at the peak of DC expansion (day 12 postlymphopenia) induced inflammatory cytokine production and increases in the number of activated DCs in lymph nodes. Importantly, boosting with gp100(25-33) melanoma peptide combined with poly(I:C) 12 days after an initial priming with the same regimen significantly increased the expansion and the antitumor efficacy of adoptively transferred pmel-1 CD8(+) T cells. These responses were abrogated after depletion of activated DCs during Ag boosting. In conclusion, our data show that CTX treatment induces, during the restoration phase, expansion of immature DCs, which are functional and can be exploited in vivo to foster more effective antitumor adoptive immunotherapy strategies.
Salem
Mohamed L
ML
Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. salemm@musc.edu
Díaz-Montero
C Marcela
CM
Al-Khami
Amir A
AA
El-Naggar
Sabry A
SA
Naga
Osama
O
Montero
Alberto J
AJ
Khafagy
Ahmed
A
Cole
David J
DJ
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D019496:Cancer Vaccines / Q000276:immunology*; D003520:Cyclophosphamide / Q000633:toxicity*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000633:toxicity*; D016219:Immunotherapy, Adoptive / Q000379:methods; D007369:Interferon Inducers / Q000276:immunology; D008231:Lymphopenia / Q000139:chemically induced; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D011070:Poly I-C / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology; D019172:Transplantation Conditioning / Q000379:methods*; D058951:gp100 Melanoma Antigen
D019496:Cancer Vaccines; D007166:Immunosuppressive Agents; D007369:Interferon Inducers; D008562:Membrane Glycoproteins; C548642:Pmel protein, mouse; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D058951:gp100 Melanoma Antigen; D003520:Cyclophosphamide; D011070:Poly I-C