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Memory Th1 Cells Augment Tumor-Specific CTL following Transcutaneous Peptide Immunization

¹ Department of Immunotherapeutics (Medinet), Graduate School of Medicine, The University of Tokyo; ² Medinet Medical Institute, MEDINET Co., Ltd.; ³ Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan; and ⁴ Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan

Requests for reprints: Kazuhiro Kakimi, Department of Immunotherapeutics (Medinet), Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-8655, Japan. Phone: 81-35805-3161; Fax: 81-35805-3164; E-mail: kakimi{at}m.u-tokyo.ac.jp.

Key Words: CTL • Th1 • TLR7 • Transcutaneous immunization • tumor immunity

Targeting dendritic cells in vivo by transcutaneous peptide immunization (TCI) represents an efficient immunization strategy to induce tumor-specific CTL because it reflects the physiologic conditions occurring during pathogen infection. Here we show that including a Th1 peptide in TCI can activate preexisting memory Th1 (mTh1) responses and thereby enhance the CTL response. For this purpose, peptide-25, a major Th1 epitope of Ag85B from Mycobacterium tuberculosis, was selected. We adoptively transferred peptide-25–specific mTh1 cells and hgp100-specific naive CTL (pmel-1 TCR transgenic) into C57BL/6 mice. Subsequently, mice were transcutaneously immunized with CTL peptide (hgp100) and Th1 peptide (peptide-25). Five days after TCI, the frequency and function of pmel-1 cells was monitored by intracellular IFN- staining, ELISPOT, and in vivo cytotoxicity assays. TCI efficiently expanded hgp100-specific, IFN-–producing, strongly cytotoxic CD8⁺ T cells. Concurrent activation of mTh1 cells by peptide-25 induced a 1.5-fold increase in the number of hgp100-specific CTL with enhanced effector functions. Furthermore, TCI elicited not only prophylactic but also therapeutic antitumor responses that were augmented by peptide-25. These results show that TCI facilitates peptide-specific activation of CD4⁺ T cells, responsible for the augmenting effect of peptide-25 on the hgp100-specific CTL response. Because a significant proportion of the Japanese population has been vaccinated with Bacillus Calmette-Guerin, they are likely to possess Ag85B- or peptide-25–specific mTh1 cells. Therefore, concomitant activation of Ag85B- or peptide-25–specific mTh1 cells together with tumor-specific CTL by TCI might augment antitumor immune responses in a sizeable fraction of patients. [Cancer Res 2008;68(10):3941–9]