title: Cyclophosphamide plus tumor necrosis factor-alpha chemoimmunotherapy cured mice: life-long immunity and rejection of re-implanted primary lymphoma.
abstract: Changes in functionally and phenotypically definable splenocyte subsets in aging mice which had been rendered tumor-free in early life by immunochemotherapy (cyclophosphamide plus tumor necrosis factor-alpha) were studied in the syngeneic EL4 lymphoma-C57BL/6 murine model. Treatment-induced long-term survivors (LTS) surviving rechallenge are termed "immune-LTS". On day 120 (day 0, initial tumor inoculation), splenocytes from day 60 rechallenged immune-LTS developed significantly greater specific anti-EL4 cytolytic activity in an ex vitro assay than those from non-rechallenged LTS. Splenocytes from combination-treated groups developed significantly higher activity than those from cyclophosphamide-induced immune-LTS. The splenic effector precursor was a CD8+ T cell. The specific anti-EL4 effector cell from the cyclophosphamide-induced immune-LTS was CD4- CD8+; however, approximately 50% of those from combination-treated immune-LTS appeared to be CD4+CD8+. On day 520 immune-LTS were randomized into 2 groups. One group was re-implanted with EL4 tumor; all mice survived. The other group was killed and, even though their splenocytes developed considerable anti-EL4 activity, their allogeneic responsiveness was as reduced as that of age-matched controls. Phenotypic analysis, compared with splenocytes from young and age-matched controls, revealed changes in the makeup of each T-cell subset, except the CD4+CD8+, and all subsets, except the CD4-CD8-, had increases in CD44 positivity. On day 625, the age of these mice was equivalent to the median life-span of C57BL/6 mice; nevertheless, their splenocytes developed high anti-EL4 activity. Phenotypic analysis indicated that, compared to day 520, there was a major decrease in CD4-CD8+ splenocytes; we suggest that these cells had migrated to the site of tumor eradication.
authors.affiliation: Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Ehrke
authors.forename: S
authors.initials: S
authors.lastname: Verstovsek
authors.forename: C M
authors.initials: CM
authors.lastname: Krawczyk
authors.forename: P
authors.initials: P
authors.lastname: Ujházy
authors.forename: G
authors.initials: G
authors.lastname: Zaleskis
authors.forename: D L
authors.initials: DL
authors.lastname: Maccubbin
authors.forename: E
authors.initials: E
authors.lastname: Mihich
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage*; D005260:Female; D006084:Graft Rejection; D008214:Lymphocytes / Q000276:immunology; D008223:Lymphoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
chemical_list: D015703:Antigens, CD; D014409:Tumor Necrosis Factor-alpha; D003520:Cyclophosphamide