Tumor growth inhibition mediated by lymphotoxin: evidence of B lymphocyte involvement in the antitumor response.
The antitumor effect of lymphotoxin (LT) and the underlying cellular mechanism were analyzed. To achieve an increased local concentration of LT at the site of tumor growth, which mimics the physiological fashion of cytokine action, we transfected the murine plasmacytoma J558L cells with a human LT expression plasmid and selected several clones that produce varying levels of LT for analysis of their tumorigenicity. The LT produced by the transfected J558L cells effectively suppressed tumor growth in syngeneic BALB/c mice without any obvious side effects. This antitumor function is indirect and LT specific, because the tumor cells did not show altered growth kinetics after the gene transfer in vitro, and tumor growth inhibition in vivo could partially be reversed by an anti-LT mAb. In nude mice, LT producing tumors were initially suppressed, but most mice developed a tumor at the end of the study. However, the requirement of T cells for complete tumor rejection could be compensated for by higher amounts of LT secretion. Furthermore, the antitumor activity of LT seems to involve B lymphocytes in the absence of functional T lymphocytes since a significant difference existed between tumor growth of J558-LT cells in nude and in SCID mice. LT-producing tumors but not parental tumors were massively infiltrated by B220+ cells in nude mice. The secretion of LT by tumor cells also induced a heavy infiltration of Mac-1+ and Mac-3+ cells and a moderate infiltration of Gr-1+ cells, both in nude and in SCID mice. Together, LT-producing J558L cells are rejected by a complex immunological mechanism, which seems to involve T as well as B and other cells. This distinguishes LT from a number of other cytokines analyzed in analogous experiments.
Qin
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Max-Delbrück-Center of Molecular Medicine, Berlin, Germany.
Blankenstein
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010954:Plasmacytoma / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D010957:Plasmids; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008233:Lymphotoxin-alpha