Capture of tumor cell membranes by trogocytosis facilitates detection and isolation of tumor-specific functional CTLs.
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.
Machlenkin
Arthur
A
Sharett Institute of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Uzana
Ronny
R
Frankenburg
Shoshana
S
Eisenberg
Galit
G
Eisenbach
Lea
L
Pitcovski
Jacob
J
Gorodetsky
Raphael
R
Nissan
Aviram
A
Peretz
Tamar
T
Lotem
Michal
M
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015550:Cell Degranulation / Q000276:immunology; D048708:Cell Growth Processes / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D051379:Mice; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology
D018984:Epitopes, T-Lymphocyte