Requirements for T cell recognition and elimination of retrovirally-transformed cells.
An adoptive therapy model has been utilized to examine the requirements for T cells to promote eradication of a disseminated, retrovirus-induced, syngeneic leukemia. Complete tumor elimination required that the transferred T cells proliferate in the host and mediate an anti-tumor effect for more than 30 days. Non-cytolytic L3T4+ T helper (Th) cells were capable of eliminating disseminated tumor without the participation of Lyt-2+ cytotoxic T cells (Tc). Purified or cloned Lyt-2+ T cells were also effective in therapy, but required the concurrent administration of either L3T4+ Th or interleukin 2 (IL-2) for optimal efficacy. L3T4+ Th appear to function via secretion of lymphokines that activate macrophages to a cytotoxic state. Lyt-2+ Tc, in addition to direct cytotoxicity, may mediate tumor eradication in part by secretion of lymphokines that activate in vivo tumoricidal macrophages. These studies suggested that the reported efficacy of individual T cell subsets in therapy of particular tumors might not reflect resistance or susceptibility to a cytotoxic effector mechanism, but rather the efficiency with which a T cell subset is activated by the tumor and/or recognizes the tumor antigen. Methods were developed to independently assess the activation and proliferation requirements of each subset. L3T4+ Th required that macrophages degrade tumor antigens in lysosomes and present the antigens in the context of class II molecules, and produced IL-2 and IL-4 as endogenous growth factors. By contrast, Lyt-2+ T cells recognized the tumor directly, required macrophages only to produce IL-1 for activation, and produced IL-2 but not IL-4 as an endogenous growth factor. The ability of T cell subsets to recognize the distinct retroviral tumor antigens expressed on FBL leukemia was assessed using cell lines or recombinant vaccinia viruses transfected with selected retroviral genes. Highly selective antigen recognition was detected, with Lyt-2+ Tc cells recognizing products of gag but not envelope genes, and L3T4+ Th recognizing envelope but not gag products. The results suggest that even complex unique tumor antigens may elicit only limited host T cell responses.
Greenberg
P
P
Division of Oncology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Klarnet
J
J
Kern
D
D
Okuno
K
K
Riddell
S
S
Cheever
M
M
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D002471:Cell Transformation, Neoplastic; D003586:Cytomegalovirus Infections / Q000628:therapy; D000939:Epitopes; D007116:Immunization, Passive; D008262:Macrophage Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*
D000951:Antigens, Neoplasm; D000939:Epitopes