Concurrent induction of CD4+ and CD8+ T cells during tumor growth with antitumor reactivity in adoptive immunotherapy.
We have previously reported that the poorly immunogenic D5 melanoma transduced to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) will elicit immunity in tumor-draining lymph node (TDLN) cells after subcutaneous inoculation. After in vitro activation with anti-CD3 and interleukin-2 (IL-2), these cells acquire in vivo antitumor reactivity to wild-type tumor in the adoptive immunotherapy of pulmonary metastases. Using monoclonal antibodies, depletion of CD4+ or CD8+ T cells immediately after the adoptive transfer of activated TDLN cells revealed that both subsets could mediate the regression of tumor in the absence of exogenous IL-2 administration. CD8+ cells were more potent than CD4+ cells in mediating tumor regression on a per cell basis. We found that the exogenous administration of IL-2 enhanced the antitumor efficacy of CD4+ T cells. Purified CD4+ and CD8+ TDLN cells that were activated separately in culture released GM-CSF and interferon-gamma in response to wild-type tumor in vitro and mediated tumor regression in vivo. Last, the induction of either immune CD4+ or CD8+ T-cell subset during growth of the GM-CSF-secreting melanoma was found to be unaffected by the depletion of the alternate T-cell subset before tumor inoculation. These findings demonstrate that both CD4+ and CD8+ T cells can independently acquire therapeutic reactivity and presumably recognize two separate epitopes involved in tumor rejection.
Arca
M J
MJ
Division of Surgical Oncology, University of Michigan, Ann Arbor 48109, U.S.A.
Krauss
J C
JC
Aruga
A
A
Cameron
M J
MJ
Chang
A E
AE
D000818:Animals; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D005260:Female; D016219:Immunotherapy, Adoptive; D018655:Lymphocyte Count; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D014407:Tumor Cells, Cultured