CD3-mediated activation of tumor-reactive lymphocytes from patients with advanced cancer.
Lymphocytes from blood or tumors of patients with advanced cancer did not proliferate and produced very low levels of tumor necrosis factor and IFN-gamma when cultured with autologous tumor cells. Proliferation and lymphokine production dramatically increased in the presence of beads conjugated with mAbs to CD3 plus mAbs to CD28 and/or CD40, and the lymphocytes destroyed the tumor cells. Expression density of CD3 concomitantly increased from low to normal levels. Furthermore, beads providing a CD3 signal (in combination with CD28 or CD28 plus CD40) gave partial protection against the inhibitory effect of transforming growth factor type beta1 on lymphocyte proliferation and production of tumor necrosis factor and IFN-gamma. MHC class I-restricted cytolytic T cells lysing autologous tumor cells in a 4-h Cr(51) release assay were generated when peripheral blood leukocytes were activated in the presence of autologous tumor cells and anti-CD3/CD28 or anti-CD3/CD28/CD40 beads. Experiments performed in a model system using anti-V-beta1 or anti-V-beta2 mAbs to activate subsets of T cells expressing restricted T cell receptor showed that lymphocytes previously activated by anti-V-beta can respond to CD3 stimulation with vigorous proliferation and lymphokine production while retaining their specificity, also in the presence of transforming growth factor type beta1. Our results suggest that T lymphocytes from cancer patients can proliferate and form Th1 type lymphokines in the presence of autologous tumor cell when properly activated, and that antigen released from killed tumor cells and presented by antigen-presenting cells in the cultures facilitates the selective expansion of tumor-directed, CD8(+) cytolytic T cells.
Hellstrom
I
I
Pacific Northwest Research Institute, 720 Broadway, and Swedish Hospital and Medical Center, Tumor Institute, 747 Broadway, Seattle, WA 98122, USA. ihellstrom@pnri.org
Ledbetter
J A
JA
Scholler
N
N
Yang
Y
Y
Ye
Z
Z
Goodman
G
G
Pullman
J
J
Hayden-Ledbetter
M
M
Hellstrom
K E
KE
D000911:Antibodies, Monoclonal / Q000276:immunology; D018106:CD28 Antigens / Q000502:physiology; D017252:CD3 Complex / Q000502:physiology*; D019013:CD40 Antigens / Q000502:physiology; D018920:Coculture Techniques; D015395:Histocompatibility Antigens Class I / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D016212:Transforming Growth Factor beta / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D019013:CD40 Antigens; D015395:Histocompatibility Antigens Class I; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma