T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor.

The results of this paper are consistent with the hypothesis that progressive growth of the Meth A fibrosarcoma evokes the generation of a T-cell-mediated mechanism of immunosuppression that prevents this highly immunogenic tumor from being rejected by its immunocompetent host. It was shown that it is possible to cause the regression of large, established Meth A tumors by intravenous infusion of tumor-sensitized T cells from immune donors, but only if the tumors are growing in T-cell-deficient recipients. It was also shown that the adoptive T-cell-mediated regression of tumors in such recipients can be prevented by prior infusion of splenic T cells from T-cell-intact, tumor-bearing donors. The results leave little doubt that the presence of suppressor T cells in T-cell-intact, tumor-bearing mice is responsible for the loss of an earlier generated state of concomitant immunity, and for the inability of intravenously infused, sensitized T cells to cause tumor regression. Because the presence of suppressor T cells generated in response to the Meth A did not suppress the capacity of Meth A-bearing mice to generate and express immunity against a tumor allograft, it is obvious that they were not in a state of generalized immunosuppression.

The immunological basis of endotoxin-induced tumor regression. Requirement for T-cell-mediated immunity.

It was shown that although intravenous administration of bacterial endotoxin caused extensive hemorrhagic necrosis of four different syngeneic murine tumors, only two of these tumors subsequently underwent complete regression: the two that were shown to be immunogeneic as classically defined. An immunologic basis for endotoxin-induced regression was further indicated by the additional findings that regression, but not hemorrhagic necrosis, of the two immunogenic tumors failed to occur in mice that were immunodepressed by whole-body gamma-irradiation, or that were made T-cell deficient by thymectomy and irradiation. That endotoxin-induced regression is T-cell mediated was suggested by the findings that tumor regression was followed by a state of long-lived immunity to a tumor cell challenge implant, and with the possession by the host of T cells that were capable of passively transferring this state of immunity to normal recipients. It is concluded that although parenteral injection of endotoxin causes hemorrhagic necrosis of most solid murine tumors, it is only those tumors that are immunogenic enough to evoke the generation of T-cell-mediated immunity which subsequently go on to completely regress.

The immunological basis of endotoxin-induced tumor regression. Requirement for a pre-existing state of concomitant anti-tumor immunity.

It was shown that of four syngeneic, murine tumors investigated, only those that evoked the generation of a state of concomitant anti-tumor immunity were susceptible to endotoxin-induced regression. Moreover, the temporal relationship between the generation of concomitant immunity and the onset of susceptibility to endotoxin-induced regression points to the likely possibility that tumor regression depends on the preceding acquisition of the specifically-sensitized, effector T cells that express concomitant immunity. It is suggested that endotoxin-induced hemorrhagic necrosis which invariably precedes tumor regression serves to create conditions inside the tumor that are conducive to the entry and the functioning of effector T cells. It is also suggested that tumor necrosis factor causes hemorrhagic necrosis rather than tumor regression.

Tumor inhibition in mice by lipopolysaccharide-induced peritoneal cells and an induced soluble factor.

Lipopolysaccharide (LPS) was shown to prevent tumor growth in BALB/c mice when administered either prior to or after the inoculation of lethal doses of tumor cells. An attempt to elucidate the mechanism of this phenomenon utilizing in vivo protocols was made by the adoptive transfer of tumor protection with peritoneal cells as well as with cell-free peritoneal fluids obtained from non-tumor-bearing, LPS-stimulated syngeneic mice. The in vivo-activated peritoneal cells from LPS-treated mice were capable of adoptively transferring tumor protection at peritoneal cell to tumor cell ratios ranging from 1,000:1 to 100:1. Experiments were also performed that indicate that: (i) LPS exerts no direct toxic or inhibitory effect on the tumor cells, and (ii) that residual LPS present in cell and fluid preparations was not responsible for such protection.

Increased toxicity of endotoxin for tumor-bearing mice and mice responding to bacterial pathogens: macrophage activation as a common denominator.

Mice bearing the syngeneic SA-1 sarcoma or treated with live Mycobacterium bovis BCG or Formalin-killed Corynebacterium parvum acquired a greatly increased susceptibility to the lethal effects of endotoxin. In all three experimental models, the acquisition of increased sensitivity to endotoxin was concordant with the generation of a systemically activated macrophage system.

Requirement for a radiosensitive lymphoid cell in the generation of lipopolysaccharide-induced rejection of a murine tumor allograft.

Lipopolysaccharide-initiated rejection of a tumor allograft requires the cooperation of a radiosensitive nonadherent lymphoid cell population and an adherent cell, presumably a macrophage.