Different tumours, transduced with different cytokine genes as G-CSF and IL-2, show inhibition of tumour take through neutrophil activation but differ in T cell functions.
The immune effectors and the cellular mechanisms responsible for tumour rejection of two different tumours transduced with different cytokines have been characterized by immunocytochemistry and in situ hybridization. A colon (C-26) and a mammary (TS/A) adenocarcinoma engineered to release, respectively, 90 pg/ml of G-CSF (C-26/G-CSF) and 30 U or 6000 U of IL-2 (low B1.30 and high B4.6000 level of IL-2, respectively) were compared for the type of infiltrating leucocytes and for the repertoire of secondary cytokines produced by the leucocytes recruited at the tumour site. The results indicate that in both systems tumour rejection is associated with prominent infiltration of CD45+/RB6-8C5+ polymorphonuclear (PMN) leucocytes expressing mRNA for IL-1 alpha, IL-1 beta and TNF alpha. TS/A B1.30 and B4.6000 also showed a small proportion of infiltrating T lymphocytes, expressing IFN gamma and IL-4 mRNA, which were virtually absent in the C-26/G-CSF tumour. In mice injected with C-26/G-CSF cells after 600 rad irradiation, the tumours grew to about 1.5 cm and then regressed completely. During the regression phase, T lymphocytes were recruited within C-26/G-CSF, and the infiltrating leucocytes were similar, in terms of PMN/macrophages/T lymphocytes ratio, to those found during the memory response elicited by injection of a challenging dose of parental TS/A into mice pre-immunized with B1.30 IL-2-producing cells. The memory response was characterized by a CD4/CD8 ratio of 0.4 and by IFN-gamma and IL-4 mRNA expression, whereas the T lymphocytes present within regressing C-26/G-CSF were mostly CD4 (CD4/CD8 ratio of 2.1) and expressed IFN gamma mRNA only. The gene transfers of cytokines as different as G-CSF and IL-2 are able to inhibit tumour take through a similar anti-tumour immune response mostly due to non-specific effectors (PMN), thus resembling acute inflammation phenomena. Regression of C-26/G-CSF initially established in irradiated mice as well as rejection of TS/A tumour injected into B1.30 immunized mice are similar to a chronic infection but the immune reaction elicited by C-26/G-CSF has an impaired T-lymphocyte function.
Stoppacciaro
A
A
Department of Human Biopathology, University of Roma.
Forni
G
G
Colombo
M P
MP
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology*; D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018375:Neutrophil Activation / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D016207:Cytokines; D007376:Interleukin-2; D012333:RNA, Messenger; D016179:Granulocyte Colony-Stimulating Factor