Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes.
Most tumor cells function poorly as antigen-presenting cells in part because they do not express costimulatory molecules. To provide costimulation to T lymphocytes that recognize tumor cells, we constructed a CD28-like receptor specific for GD2, a ganglioside overexpressed on the surface of neuroblastoma, small-cell lung carcinoma, melanoma, and other human tumors. Recognition of GD2 was provided by a single-chain antibody derived from the GD2-specific monoclonal antibody 3G6. We demonstrate that the chimeric receptor 3G6-CD28 provides CD28 signaling upon specific recognition of the GD2 antigen on tumor cells. Human primary T lymphocytes retrovirally transduced with 3G6-CD28 secrete interleukin 2, survive proapoptotic culture conditions, and selectively undergo clonal expansion in the presence of an antiidiotypic antibody specific for 3G6-CD28. Polyclonal CD8(+) lymphocytes expressing 3G6-CD28 are selectively expanded when cultured with cells expressing allogeneic major histocompatibility complex class I together with GD2. Primary T cells given such an antigen-dependent survival advantage should be very useful to augment immune responses against tumor cells.
Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
A
A
Krause
H F
HF
Guo
J B
JB
Latouche
C
C
Tan
N K
NK
Cheung
M
M
Sadelain
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D017209:Apoptosis; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D005732:Gangliosides / Q000276:immunology / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D010455:Peptides / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D000888:Antibodies, Anti-Idiotypic; D018106:CD28 Antigens; D017252:CD3 Complex; D005732:Gangliosides; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D010455:Peptides; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; C019403:ganglioside, GD2