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Capture of Tumor Cell Membranes by Trogocytosis Facilitates Detection and Isolation of Tumor-Specific Functional CTLs

¹ Sharett Institute of Oncology and ² Department of Surgery, Hadassah-Hebrew University Hospital, Jerusalem, Israel; ³ Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; and ⁴ Migal, Kiryat Shmona, Israel

Requests for reprints: Michal Lotem and Arthur Machlenkin, Sharett Institute of Oncology, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel. Phone: 972-2-6776781; Fax: 972-2-6422794; E-mail: mlotem{at}hadassah.org.il and arthurm{at}hadassah.org.il.

Key Words: trogocytosis • adoptive cell transfer • cellular immunotherapy • immune responses to cancer • tumor immunobiology

The success of adoptive cell transfer in the treatment of metastatic cancer in humans is dependent on the selection of highly active tumor-specific cytotoxic T cells. We report here that CTLs capture membrane fragments from their targets while exerting cytotoxic activity and thus gain a detectable functional signature by which they can be identified. Fluorochrome labeling or biotinylation was used to tag tumor cells. CD8⁺ T cells were coincubated with the tagged targets, sorted, and functionally evaluated. Our results show that membrane capture by CD8⁺ lymphocytes is T-cell receptor dependent, epitope specific, and preferentially associated with highly cytotoxic clonal subsets. CTLs that captured membranes from unmodified melanoma exhibited enhanced cytotoxic activity against tumor cell lines and autologous melanoma. In a human melanoma in vivo model, adoptive transfer of membrane-capturing, peptide-specific T cells, but not noncapturing or bulk CD8⁺ T cells, inhibits tumor progression. Membrane capture is therefore a signature of antigen-specific CTLs endowed with high functional avidity and may have direct relevance in the clinical application of adoptive immunotherapy. [Cancer Res 2008;68(6):2006–13]