Presence of cytotoxic B220+CD3+CD4-CD8- cells correlates with the therapeutic efficacy of lymphoma treatment with IL-2 and/or IL-12.
Cancer treatment with IL-2 and IL-12 is thought to work via enhancement of proliferation and activity of T cells and NK cells. Incubation of cytotoxic T lymphocytes (CTLs) and NK cells with IL-2 and/or IL-12 results in propagation of a distinct cell type called lymphokine-activated killers (LAK) characterized by increased lytic activity against many tumor types. Here we address the question whether cytokine therapy may be efficient in treatment of a LAK-insensitive tumor and, if so, which cell type, other than classic LAK cells, is responsible for tumor cell killing. We used DBA/2 mice bearing metastasized SL2 lymphoma and treated them with locally applied IL-2 and /or IL-12 injections. We showed that IL-12 treatment is efficient, though there is a rather narrow range of effective doses because of toxicity. This toxicity may be alleviated by a single injection of IL-12 before treatment. Next, we showed that IL-12 synergistically enhances the efficacy of local IL-2 treatment. Moreover, our results indicate that the IL-2/IL-12-mediated therapeutic effect is greatest when it is given after establishment of an immune response to a tumor. Finally, we showed the existence of a unique population of lymphoid cells, namely B220+CD3+CD4-CD8-, at the site of tumor growth. These cells become highly cytotoxic to SL2 cells in mice treated with cytokines late (day 10-14) in the course of the immune response, but not in mice treated early (day 3-7), and cytotoxicity of this unique cell population correlates with the success of therapy.
Masztalerz
Agnieszka
A
Department of Biochemistry and Cell Biology, University of Utrecht, The Netherlands. a.masztalerz@vet.uu.nl
Everse
Linda Ann
LA
Otter
Willem Den
WD
D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis*; D015704:CD4 Antigens / Q000096:biosynthesis*; D016827:CD8 Antigens / Q000096:biosynthesis*; D002448:Cell Adhesion; D002455:Cell Division; D045744:Cell Line, Tumor; D016207:Cytokines / Q000627:therapeutic use; D005260:Female; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000096:biosynthesis*; D008214:Lymphocytes / Q000276:immunology; D008223:Lymphoma / Q000628:therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy; D010641:Phenotype; D010919:Placebos; D013997:Time Factors
D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D007376:Interleukin-2; D010919:Placebos; D018664:Interleukin-12; D017493:Leukocyte Common Antigens