Tumor expression of 4-1BB ligand sustains tumor lytic T cells.
Inadequate costimulation by solid tumors is generally believed to induce immune tolerance during primary tumor growth. We looked for tumor-specific immunity vs. tolerance in patients with Ewing's sarcoma. Circulating T cells from patients with progressively growing Ewing's tumors displayed MHC restricted tumor-induced proliferation and robust tumor lysis. Tumor-reactive T cells reside within the memory CD3+CD8+ subset and are CD28-/4-1BB+. Autologous Ewing's tumors expressed 4-1BBL, and tumor-induced T cell proliferation and activation required costimulation by 4-1BBL. Stimulation of PBL with anti-CD3/4-1BBL, but not anti-CD3/anti-CD28 induced tumor lytic effectors. Similarly, in a xenograft model, anti-CD3/4-1BBL expanded T cells controlled primary growth and prevented metastasis of autologous tumors while nonactivated and anti-CD3/anti-CD28 activated CD8+ cells did not. These results question prevailing models of tumor induced tolerance accompanying progressive tumor growth; rather, we show coexistence of progressive tumor growth and anti-tumor immunity, with costimulation provided by the tumor itself. They further demonstrate a potential new therapeutic role for 4-1BBL mediated costimulation in expanding tumor reactive CTLs for use in the adoptive immunotherapy of cancer.
Zhang
Hua
H
National Cancer Institute; Bethesda, Maryland USA.
Merchant
Melinda S
MS
Chua
Kevin S
KS
Khanna
Chand
C
Helman
Lee J
LJ
Telford
Bill
B
Ward
Yvona
Y
Summers
Jeffrey
J
Toretsky
Jeff
J
Thomas
Elaine K
EK
June
Carl H
CH
Mackall
Crystal L
CL
D053330:4-1BB Ligand; D000293:Adolescent; D000328:Adult; D000818:Animals; D001859:Bone Neoplasms / Q000276:immunology* / Q000517:prevention & control; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000276:immunology* / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D053330:4-1BB Ligand; D018106:CD28 Antigens; D017252:CD3 Complex; D016827:CD8 Antigens; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; C505974:TNFSF9 protein, human; C505975:Tnfsf9 protein, mouse; D014409:Tumor Necrosis Factor-alpha