Therapeutic effects of tumor reactive CD4+ cells generated from tumor-primed lymph nodes using anti-CD3/anti-CD28 monoclonal antibodies.
T-cell activation involves multiple signaling pathways. In this report, we conducted in vitro and in vivo immune function analysis of tumor-draining lymph node (TDLN) cells after anti-CD3/anti-CD28 activation versus anti-CD3 activation alone in a murine tumor model. In cytokine release assays, the doubly activated TDLN cells secreted significantly greater amounts of IFN-gamma and GM-CSF in response to specific tumor antigen compared with anti-CD3 activated cells. In adoptive immunotherapy, the doubly activated TDLN cells were more effective in mediating regression of 3-day pulmonary metastases compared with anti-CD3 activated cells. Although there was predominant proliferation of CD8+ cells after either activation procedure, the mean-fold expansion of CD4+ cells was significantly greater after anti-CD3/anti-CD28 activation than anti-CD3 activation alone. Using magnetic bead-enriched T-cell subsets, we found that either CD4+ or CD8+ doubly activated TDLN cells could independently mediate tumor regression. Furthermore, the doubly activated CD4+ cells were more effective than CD8+ cells in adoptive immunotherapy on a per-cell basis. The antitumor activity mediated by CD4+ or CD8+ cells could be significantly enhanced with the exogenous administration of IL-2. CD28 co-stimulation of tumor-primed lymphoid cells promotes the generation of potent tumor reactive effector cells, particularly CD4+ T cells, with antitumor activity in adoptive immunotherapy.
Li
Qiao
Q
The Division of Surgical Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor 48109-0666, USA. qiaoli@umich.edu
Yu
Bo
B
Grover
Amelia C
AC
Zeng
Xianying
X
Chang
Alfred E
AE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2