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Tumors Hamper the Immunogenic Competence of CD4⁺ T Cell-Directed Dendritic Cell Vaccination¹

Valérie S. Zimmermann^2,*, Anna Casati^3,*, Chris Schiering^*,, Stefano Caserta^*,, Rodrigo Hess Michelini^*,, Veronica Basso^* and Anna Mondino^4,*

^* Cancer Immunotherapy and Gene Therapy Program, San Raffaele Scientific Institute, Department of Biotechnology, Milan, Italy; University of Glasgow, Scotland, United Kingdom; University "Vita e Salute", Milan, Italy; and Open University and University "Vita e Salute", Milan, Italy.

Dendritic cells loaded with tumor-derived peptides induce protective CTL responses and are under evaluation in clinical trails. We report in this study that prophylactic administration of dendritic cells loaded with a MHC class II-restricted peptide derived from a model tumor Ag (Leishmania receptor for activated C kinase (LACK)) confers protection against LACK-expressing TS/A tumors, whereas therapeutic vaccination fails to cure tumor-bearing mice. Although CD4⁺ T cell-directed dendritic cell vaccination primed effector-like (CD44^highCD62L^low, IL-2⁺, IFN-⁺) and central memory-like lymphocytes (CD44^highCD62L^high, only IL-2⁺) in tumor-free mice, this was not the case in tumor-bearing animals in which both priming and persistence of CD4⁺ T cell memory were suppressed. Suppression was specific for the tumor-associated Ag LACK, and did not depend on CD25⁺ T cells. Because T cell help is needed for protective immunity, we speculate that the ability of tumors to limit vaccine-induced CD4⁺ T cell memory could provide a partial explanation for the limited efficacy of current 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 grants from the Associazione Italiana Ricerca sul Cancro, Compagnia San Paolo Istituto Mobiliare Italiano, Italian Ministry of Education (Ministero dell’Istruzione, dell’Università e della Ricerca (FIRB-RBNE017) and the European Community (contract LSHC-CT-2005-018914 "ATTACK").

² Current address: Immunomodulation and Immunotherapy, Institut de Génétique Moléculaire de Montpellier, 1919, Route de Mende, 34293 Montpellier CEDEX 5.

³ Current address: Institute for Research in Biomedicine, Via Vincenzo Vela 6, Bellinzona CH-6500 Switzerland.

⁴ Address correspondence and reprint requests to Dr. Anna Mondino, Cancer Immunotherapy and Gene Therapy Program, San Raffaele Scientific Institute, Via Olgettina, 58, 20132 Milan, Italy. E-mail address: anna.mondino{at}hsr.it

⁵ Abbreviations used in this paper: LACK, Leishmania receptor for activated C kinase; DC, dendritic cell; LN, lymph node; Tg, transgenic.

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