Immunomodulation of the Lymphoresponsive Phases of Carcinogenesis: Mechanisms of Natural Immunity<xref ref-type="fn" rid="fn2">2</xref>

Abstract

Biphasic modulation of the frequency of 3-methylcholanthrene-induced tumors in relation to increasing immunocompetence of tumor-bearing mice is indicative of lymphoresponsive stimulatory and inhibitory phases of carcinogenesis; components and mechanisms contributing to the paradoxical ability of the native or natural immune system to stimulate as well as to inhibit the development of cancer were identified with the use of an in vitro model of carcinogenesis. Normal NIH/N Syrian golden hamster spleen leukocytes caused a biphasic modulation of UV-irradiated hamster cell morphologic transformation that was dependent on the leukocyte-to-target cell (L:TC) ratio. Whereas low (less than 50:1) and high (greater than 200:1) L:TC ratios inhibited the transformation frequency, intermediate ratios were less inhibitory and seemingly immunostimulatory. Inhibition alone occurred with antigen- or mitogen-activated leukocytes or with macrophages. An anticarcinogenic lymphocyte hormone, lymphotoxin, eliminated the leukocyte-mediated stimulatory phase; galactose, a lymphotoxin inhibitor, blocked the leukocyte-mediated inhibitory phases. Thus immunoinhibition was mediated through lymphotoxin, and the apparent immunostimulation possibly resulted from immune cell regulation of lymphotoxin activity during the early stages of carcinogenesis.