Subversive Activity of Syngeneic Tumor Cells as an Escape Mechanism From Immune Surveillance and the Role of Prostaglandins*

Abstract

Mice bearing a syngeneic tumor become increasingly immunodepressed during growth of the tumor, being unable to develop both cellular and humoral immunity to a histoincompatible tumor allograft and to reject the allograft. This failure to reject a strongly antigenic tumor allograft suggests that immunodepression associated with growth of a weakly antigenic syngeneic tumor provides the syngeneic tumor with an escape mechanism. This immunodepression is also manifest by the suppression of the response of spleen cells to mitogen stimulation by syngeneic tumor cells, both in vivo and in vitro. T cells that are stimulated by PHA, a T-cell mitogen, are the primary targets, and their suppression is the result of the direct subversive activity of the tumor cells. Subversion of T cells by tumor cells seems to be mediated through the prostaglandin pathway, because the prostaglandin PGE2 is itself suppressive, and an antagonist of PGE2 and an inhibitor of prostaglandin synthetases both inhibit the subversive activity of tumor cells. Several tumor cell lines tested, of different etiology and histologic type, all were subversive. This suggests that this subversive activity may be a general property of tumor cells and may be a key element in their ability to thwart the immunological system of the host. For this reason, any therapeutic regimen of cancer, based on immunostimulating drugs, should include drugs that can inhibit active subversion of the immune system by the tumor itself. Antagonists of prostaglandins and inhibitors of prostaglandin synthetases show promise in this regard.

Interaction between two cellular subpopulations of a rat colonic carcinoma when inoculated to the syngeneic host

“…In other models, progressive tumors have been reported to produce soluble factors able to inhibit tumoricidal activities of T lymphocytes (Hellstrom and Hellstrom, 1970), macrophages (Cheung et al, 1979) and NK cells (Keong et al, 1983), or to prevent accumulation of tumoricidal macrophages at sites of inflammation (Fauve et al, 1974;Snyderman and Pike, 1976;Pasternack et al, 1978). Prostaglandins have been thought to be one of the potential immunosuppressive factors elaborated by progressive tumors (Plescia et al, 1976). However, prostaglandins do not play an important role in our model since TR cell growth in vivo is not significantly modified by indomethacin, a potent inhibitor of prostaglandin synthesis (Olsson et al, 1984).…”

“…Prostaglandins have been thought to be one of the potential immunosuppressive factors elaborated by progressive tumors (Plescia et al, 1976). However, prostaglandins do not play an important role in our model since TR cell growth in vivo is not significantly modified by indomethacin, a potent inhibitor of prostaglandin synthesis (Olsson et al, 1984).…”

Immunosuppresive Factors in Cancer

“…7.4.2.2 Effects of PGE 2 on T lymphocytes PGE 2 is immunosuppressive to various types of T cells through its inhibitory effects on proliferation, cytokine production, migration and effector activity (reviewed in [229,230]). Very early studies showed that immunization with PGE 2 significantly reduced tumor-induced immunosuppression (as measured by spleen cell proliferation assays) in mice [231,232], suggesting the role of PGE 2 in suppressing T cell proliferation. Further studies using experimental tumor models and anti-PGE 2 antibodies demonstrated the role of PGE 2 in suppressing polyclonal T cell activation and CTL generation following MLRs by splenic T cells [233].…”

Inhibition of interleukin 2 production by prostaglandin E2 is not absolute but depends on the strength of the stimulating signal

“…Patients with Hodgkin's disease have been found to contain prostaglandin-producing suppressor cells which are believed to be responsible for the depressed cellular immunity in these patients (4). It has also been reported that prostaglandins inhibit the rejection of tumors (3,5); and prostaglandin of the E series, PGEl and PGE2, have been shown to inhibit the activation of cytotoxic T lymphocytes (CTL) (6,7). Prostaglandins have been shown to inhibit the proliferative response of lymphoid cells including interleukin-Z dependent cytolytic T-cell lines (8)(9)(10)(11)(12), reviewed in ( 1, 13)); and indomethacin and other inhibitors of prostaglandin synthesis have been shown to enhance the induction of cytotoxic responses against allogeneic cells (10).…”