Enhancement of immune reactivity in the lymph nodes draining a murine melanoma engineered to elaborate interleukin-4.
The adoptive transfer of immune T cells has been demonstrated to mediate regression of established tumors in animals, with encouraging results in human clinical trials. In animal studies, lymph nodes (LN) draining a progressively growing immunogenic tumor contain tumor-sensitized but functionally deficient T cells. These "preeffector" cells can be activated in vitro by sequential stimulation with anti-CD3 and interleukin (IL)-2 to differentiate into mature effector cells capable of mediating the regression of disseminated tumor. However, the preeffector cell response is weak during the growth of poorly immunogenic tumors such as the B16-BL6 melanoma. In this study, a clone of B16-BL6, A9, was transfected with the cDNA encoding for murine IL-4, in an attempt to enhance tumor immunogenicity. IL-4 secreting clones grew significantly slower than controls after intradermal (i.d.) inoculation, but all animals eventually succumbed to the progressive tumor. The ability of IL-4-secreting tumor cells to stimulate a preeffector cell response was then investigated. LN draining the IL-4-secreting tumors for 10 days were activated by the anti-CD3/IL-2 method. The resulting lymphocytes were adoptively transferred into animals bearing 3-day established parental pulmonary metastases. The transfer of cells derived from sensitization with the IL-4-secreting tumors was capable of significantly reducing the numbers of pulmonary metastases more effectively than cells sensitized to the parental tumor. Thus, genetic modification of tumor cells to secrete IL-4 can stimulate an increase in the preeffector cell response in the tumor-draining LN, suggesting an enhancement in T-cell-mediated immune function against the parental tumor.
Krauss
J C
JC
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Strome
S E
SE
Chang
A E
AE
Shu
S
S
D000818:Animals; D017252:CD3 Complex / Q000276:immunology; D005260:Female; D015316:Genetic Therapy; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008198:Lymph Nodes / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D014162:Transfection; D014407:Tumor Cells, Cultured
D017252:CD3 Complex; D007376:Interleukin-2; D015847:Interleukin-4