Immunoregulation in cancer-bearing hosts. Down-regulation of gene expression and cytotoxic function in CD8+ T cells.
The causes of the decreased immune responsiveness in tumor-bearing hosts are incompletely understood. The impact of a decreased immune response in cancer patients on the clinical response in immunotherapy trials has not been evaluated. The present report demonstrates a marked decrease in the therapeutic efficacy of adoptively transferred T lymphocytes obtained from murine hosts bearing tumor for greater than 30 days [late tumor-bearing mice (TBM)] as compared with normal mice and mice bearing tumor for less than 21 days (early TBM). In vitro analysis of the functions of the T lymphocytes from late TBM showed an apparently normal proliferative response to anti-CD3 and IL-2 with adequate lymphokine production from CD4+ cells, but a significant decrease in the cytotoxic function of CD8+ cells. The decreased cytotoxicity was not because of cell-mediated suppression. The expression of granzyme B mRNA was significantly delayed and decreased in magnitude in CD8+ cells from late TBM. Culture supernatants from two unrelated tumor cell lines were able to inhibit the cytotoxic activity of normal CD8+ cells in vitro. The tumor-derived suppressive factor is not transforming growth factor-beta (TGF-beta), but it has not been further characterized. The data suggest that one potential mechanism responsible for immunologic defects in patients with large tumor burdens is a tumor-induced defect that compromises the function of CD8+ effector T cells.
Immunotherapy Laboratory, Program Resources, Inc./DynCorp, Frederick, MD 21702.
C M
CM
Loeffler
M J
MJ
Smyth
D L
DL
Longo
W C
WC
Kopp
L K
LK
Harvey
H R
HR
Tribble
J E
JE
Tase
W J
WJ
Urba
A S
AS
Leonard
H A
HA
Young
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens / Q000032:analysis; D002277:Carcinoma / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D053804:Granzymes; D007116:Immunization, Passive; D066298:In Vitro Techniques; D008211:Lymphocyte Cooperation; D008223:Lymphoma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D016827:CD8 Antigens; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases