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Phenotype and Homing of CD4 Tumor-Specific T Cells Is Modulated by Tumor Bulk¹

Fabio Benigni^2,3,*, Valérie S. Zimmermann^3,*, Stephanie Hugues^4,, Stefano Caserta^*,, Veronica Basso^*, Laura Rivino^5,*, Elizabeth Ingulli, Laurent Malherbe, Nicolas Glaichenhaus and Anna Mondino^6,*

^* Cancer Immunotherapy and Gene Therapy Program, S. Raffaele Scientific Institute, Milan, Italy; Institut National de la Recherche Médicale, Université de Nice-Sophia Antipolis, Valbonne, France; International Ph.D. Program in Molecular Medicine, University Vita e Salute, Milan, Italy; and Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455

Technical difficulties in tracking endogenous CD4 T lymphocytes have limited the characterization of tumor-specific CD4 T cell responses. Using fluorescent MHC class II/peptide multimers, we defined the fate of endogenous Leishmania receptor for activated C kinase (LACK)-specific CD4 T cells in mice bearing LACK-expressing TS/A tumors. LACK-specific CD44^highCD62L^low CD4 T cells accumulated in the draining lymph nodes and had characteristics of effector cells, secreting IL-2 and IFN- upon Ag restimulation. Increased frequencies of CD44^highCD62L^low LACK-experienced cells were also detected in the spleen, lung, liver, and tumor itself, but not in nondraining lymph nodes, where the cells maintained a naive phenotype. The absence of systemic redistribution of LACK-specific memory T cells correlated with the presence of tumor. Indeed, LACK-specific CD4 T cells with central memory features (IL-2⁺IFN-^–CD44^highCD62L^high cells) accumulated in all peripheral lymph nodes of mice immunized with LACK-pulsed dendritic cells and after tumor resection. Together, our data demonstrate that although tumor-specific CD4 effector T cells producing IFN- are continuously generated in the presence of tumor, central memory CD4 T cells accumulate only after tumor resection. Thus, the continuous stimulation of tumor-specific CD4 T cells in tumor-bearing mice appears to hinder the systemic accumulation of central memory CD4 T lymphocytes.

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