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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)¹

Mohamed L. Salem^*,,2, C. Marcela Díaz-Montero^*, Amir A. Al-Khami^*,, Sabry A. El-Naggar^*,, Osama Naga^*, Alberto J. Montero, Ahmed Khafagy and David J. Cole^*

^* Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425; Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425; Zoology Department, Faculty of Science, Tanta University, Egypt; and Microbiology Department, Faculty of Veterinary Medicine, Suez Canal University, Egypt

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health Grant 1 R01 CA94856-01.

² Address correspondence and reprint requests to Dr. Mohamed L. Salem, Department of Surgery, Medical University of South Carolina, Charleston, SC 29425. E-mail address: salemm{at}musc.edu

³ Abbreviations used in this paper: TBI, total body irradiation; BM, bone marrow; cDC, conventional DC; CTX, cyclophosphamide; DC, dendritic cell; DTx, diphtheria toxin; DTR, diphtheria toxin receptor; LN, lymph node; OVAp, OVA albumin peptide; PBL, peripheral blood leukocyte; pDC, plasmacytoid DC; Tg, transgenic; TLRL, TLR ligand; TLR3L, TLR 3 ligand.

⁴ The online version of this article contains supplemental material.