In vitro analysis of cancer prevention by a mycobacterial antigen complex and of cancer-promoted inhibition of immune reactions

Abstract

The antigen complex A60 of Mycobacterium bovis bacillus Calmette-Guérin protected mice against experimental tuberculous infection, and prevented cancer development after challenge with EMT 6 cells. Although humoral and cellular immune reactions elicited by A60 in vivo remained unaffected in cases of tumor rejection, they were suppressed in the case of neoplastic growth. In the present work, these in vivo observations were analyzed by in vitro techniques. Activated macrophages played a major role, and cytolytic T lymphocytes a minor role, in A60-promoted cancer cell cytolysis leading to tumor rejection. In vitro, EMT 6 cells weakly inhibited the proliferation of A60-specific B lymphocytes and strongly inhibited the functions of activated macrophages. However, the collapse of both humoral and cellular immune reactions during the course of cancer development was also accompanied by an inhibitory action of EMT 6 cells on the multiplication and functions of A60-specific T lymphocytes. Tumor-dependent repression of macrophage activation was therefore due to both a direct action of tumor cells on macrophages and an indirect one via inhibition of macrophage-activating T cell functions. On the other hand, tumor-induced collapse of the anti-A60 Ig synthesis was mainly due to inhibition of B-cell-activating T cells, with a weaker direct effect of tumor cells on B lymphocytes. Consequently, A60 and tumor cells exert opposite effects on the immune system at several levels.

Synthesis of Cytokines During Tumour Development in Mice Immunized with the Mycobacterial Antigen Complex A60

“…Previous studies [14] have shown that A60 successfully protects 60-70% of the mice from tumour challenge. The tumour cells are able to develop as lethal cancers in the remainder of cases, primarily by a process involving inhibition of the activation and function of both T lymphocytes and M8s [14,31].…”

Immunological relatedness of the protective mechanisms against tuberculosis and cancer

“…The cytolytic ability of CTL (A) and MΦ (B) were then measured by a chromium release assay, using labelled EMT 6 cells as targets. The activating action of A60 on cytolytic cells [ 80] is evident.…”

“…On the contrary, B‐cell activation by specific T cells previously incubated with tumour cells was clearly inhibited ( Fig. 6B) [ 80]. Consequently, the tumour‐promoted alteration of the humoral immune system seems to be due to an inhibitory interaction of cancer cells with T lymphocytes ( Fig.…”

“…Macrophage cytotoxicity was then monitored by a chromium release assay using labelled EMT 6 cells as targets. Note the inhibitory effect of tumour cells on TL proliferation (A) and on TL‐dependent B‐cell (B) and MΦ (C) activation [ 80].…”

“…When MΦ from competent mice were pre‐incubated with EMT 6 tumour cells before contact with A60‐stimulated T lymphocytes, their performance was clearly impaired ( Fig. 6C, Table 3) [ 80]. All the specific functions of activated MΦ, be it tumour cytolysis or production of oxygen and nitrogen radicals, were reduced in MΦ confronted with cancer cells.…”