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Helper Function of Memory CD8⁺ T Cells: Heterologous CD8⁺ T Cells Support the Induction of Therapeutic Cancer Immunity

Departments of ¹ Surgery, ² Ophtalmology, ³ Dermatology, ⁴ Immunology, and ⁵ Infectious Diseases and Microbiology, University of Pittsburgh; ⁶ Eye and Ear Institute; and ⁷ University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

Requests for reprints: Pawel Kalinski, Department of Surgery, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Research Pavilion, Room 1.46b, 5117 Center Avenue, Pittsburgh, PA 15213-1863. Phone: 412-648-8957; Fax: 412-648-1077; E-mail: kalinskip{at}upmc.edu.

In contrast to the well-established efficacy of preventive vaccines, the effectiveness of therapeutic vaccines remains limited. To develop effective vaccination regimens against cancer, we have analyzed the effect of effector and memory CD8⁺ T cells on the ability of dendritic cells to mediate the immunologic and antitumor effects of vaccination. We show that in contrast to effector CD8⁺ T cells that kill antigen-carrying dendritic cells, IFN-producing memory CD8⁺ T cells act as "helper" cells, supporting the ability of dendritic cells to produce interleukin-12 (IL-12) p70. Promoting the interaction of tumor antigen-carrying dendritic cells with memory-type "heterologous" (tumor-irrelevant) CD8⁺ T cells strongly enhances the IL-12p70-dependent immunogenic and therapeutic effects of vaccination in the animals bearing established tumors. Our data show that the suppressive and helper functions of CD8⁺ T cells are differentially expressed at different phases of CD8⁺ T-cell responses. Selective performance of helper functions by memory (in contrast to effector) CD8⁺ T cells helps to explain the phenomenon of immune memory and facilitates the design of effective therapeutic vaccines against cancer and chronic infections. [Cancer Res 2007;67(20):10012–8

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