Herpes simplex virus (HSV) amplicon-mediated codelivery of secondary lymphoid tissue chemokine and CD40L results in augmented antitumor activity

Khaled A. Tolba, William J. Bowers, Jacquelyn Muller, Vickie Housekneckt, Rita E. Giuliano, Howard J. Federoff, Joseph D. Rosenblatt

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Development of effective antitumor immune responses depends on timely interactions of effector cells. A bimodal approach that involves coexpression of chemokines and costimulatory molecules within the tumor bed mav elaborate a more optimal antitumor response. One candidate includes secondary lymphoid tissue chemokine (SLC), which promotes the colocalization of naïve, nonpolarized memory T cells and dendritic cells (DCs) within lymph nodes and Peyer's patches. CD40L-mediated DC activation could induce maturation, enhance antigen presentation, and facilitate priming of the recruited naïve T cells. To this end, the antitumor activity of SLC and CD40L expressed singly or in combination using the herpes simplex virus (HSV)-derived amplicon was examined in two murine models: A20, a B-cell lymphoma, and CT-26, an adenocarcinoma. Administration of amplicons encoding SLC (HSV-SLC) into s.c. tumors established previously resulted in heavy infiltration of CD4+ and CD8+ T cells, and DCs, and the generation of cytolytic T-cell activity. Combined transduction of either tumor with HSV-SLC and HSV-CD40L resulted in a more enhanced antitumor activity that was CD8+ T cell-dependent than observed with either vector alone. mRNA expression of the Th1 markers IFN-γ, perforin, and interleukin 12 was detectable only in transduced regressing tumors. In addition to identifying a potent antitumor immune strategy, we show that amplicon-mediated SLC and CD40L delivery may mimic lymph node conditions necessary for priming naïve T cells within the tumor bed, and demonstrate the importance of DC activation status on antigen presentation and cytokine expression for priming of newly recruited T cells.

Original languageEnglish (US)
Pages (from-to)6545-6551
Number of pages7
JournalCancer Research
Volume62
Issue number22
StatePublished - Nov 15 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Tolba, K. A., Bowers, W. J., Muller, J., Housekneckt, V., Giuliano, R. E., Federoff, H. J., & Rosenblatt, J. D. (2002). Herpes simplex virus (HSV) amplicon-mediated codelivery of secondary lymphoid tissue chemokine and CD40L results in augmented antitumor activity. Cancer Research, 62(22), 6545-6551.