DISCUSSION PAPER: HUMORAL IMMUNE RESPONSES TO TUMOR-ASSOCIATED ANTIGENS E. Frederick Wheelock Department of Microbiology Je#erson Medical College Philadelphia, Pennsylvania 191 07

As with cellular immune responses, in which both cytotoxic killer cells and immune suppressor lymphocytes have been identified, the humoral response to tumor-associated antigens has been shown to function to both the benefit and the detriment of the host. In the category of humoral immune responses that have been beneficial to the host, we have heard, in the report by Dr. Hu from Dr. Lima’s laboratory, that antibody directed against cell surface antigens on tumor cells induced by reticuloendotheliosis virus can suppress the tumor after it has developed. I will describe another example from my studies. I presented evidence earlier this week, at the companion Conference on Immunobiology of Cancer,’ that doublestranded RNA from Penicillium stoloniferum mycophage can completely suppress established Friend leukemia virus (FLV) leukemia in mice and does so by acting as an adjuvant, stimulating production of an antibody that is both virus neutralizing and cytotoxic for the leukemia cells. Since many who are here today were not at the preceding conference, I will summarize that material very briefly. The antibody response to sheep erythrocytes, as measured by quantitation of hemolysin-producing spleen cells by use of the Jerne plaque technique, is depressed in FLV-infected mice and can be restored to normal levels by an RNA-rich extract from the P . stoloniferum mycophage. We have evidence that the active immunostimulatory substance is RNA. Multiple phenol extractions gave a 100-fold increase in specific activity of RNA. Spectrophotometric data confirm that the substance is RNA, and the fact that it is not be affected by RNase at high salt concentrations but is destroyed by RNase at low salt levels gives additional evidence that it is a double-stranded RNA. Administration of this RNA-rich extract after FLV results in leukemosuppression. Mice in which the FLV infection is suppressed produce high titers of antibody that are cytotoxic to FLV leukemia cells. We have good evidence that this FLV-cytotoxic antibody effects suppression of the leukemia.2 If we administer the antibody itself to FLV-infected mice, it can suppress the disease completely. Interestingly, the DBA-2 mouse is complement deficient, and we have found that DBA-2 mouse serum has potent anticomplementary activity that blocks the cytolytic action of antibody in vitro at concentrations that exist in vivo. We therefore are not quite sure how the antibody exerts its effect in vivo, but we suspect the mechanism to be antigenic modulation. Humoral immune responses may act to the detriment of the host. There are several tumor systems in which antibody is produced that is cytophilic but not cytotoxic, even in the presence of complement. The ability of such antibody or antigen-antibody complexes to block the cytotoxic action of killer lympho-

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cytes is well known. The immunopathologic effects of immune complexes on nontumor tissues, especially the kidneys, is another mechanism through which humoral immune responses may affect the host adversely. Also in this category, a noncytotoxic antibody can modulate the expression of tumor antigens at the cell surface through various mechanisms, such as capping or shedding or invagination of surface antigens, or by inhibition of the production of new cell surface antigen. This is the phenomenon of “antigenic modulation,” first reported by Old and Boyse. Presumably, tumor cells on which the tumor-associated antigens have been suppressed through modulation could escape from cell-mediated immune attack. It may be that such modulation occurs regularly during early stages of tumor growth and that later, when the tumor reaches a clinically detectable size, it may be too large for cell-mediated immune mechanisms to attack it effectively. Finally, antibody has been complexed with tumor-suppressive agents in some very clever ways to deliver these agents to the tumor site at concentrations sufficient to exert an antitumor effect. This therapeutic approach would be hindered by competition with endogenous antibody, by antigenic modulation, by adsorption of administered antibody onto tumor antigens that have been shed into the serum, or if tumor-associated antigens were concealed beneath a layer of glycoprotein. I would like to conclude by stressing the importance of studying the intact animal. This may seem like an obvious statement, but there are increasing numbers of tumor cell-inhibiting reactions that can be demonstrated in vitro under conditions that simply do not exist in the animal. I have described our experience with complement-dependent antibody in FLV leukemia. Another example is the tumor cell cytotoxic activity of sera from cancer patients that exists when tested in vitro with guinea pig or rabbit complement but that has no cytotoxic effect when human complement is used. Dr. Reif, this afternoon, also emphasized the lack of correlation between in vitro and in vivo effects of antithymocyte serum. In cellular immune reactions in vitro, there is the wellknown necessity for very high multiplicities of killer cells per target cell to achieve target cell destruction; however, these high killer cell to target cell ratios may not exist in the living animal. In vitro assays of immune responses to tumor antigens are very useful for detecting and quantitating several humoral and cellular antitumor effector mechanisms, but studies should also be performed in ways that truly reflect what is happening in the animal host. Often this cannot be done, but we should at least be aware of the limitations of in vitro assays of antitumor immune responses. REFERENCES 1. MARX, P. A. & E. F. WHEELOCK. 1976. Influence of immune stimulators on viral leukemogenesis. Ann. N.Y. Acad. Sci. 276 502-512. 2. WHEELOCK, E. F., S. T. TOY,0. S. WEISLOW & M. H. LEVY.1974. Restored immune and nonimmune functions in Friend virus leukemic mice treated with statolon. Progr. Exp. Tumor Res. 19: 369-389.

Discussion paper: humoral immune responses to tumor-associated antigens.

DISCUSSION PAPER: HUMORAL IMMUNE RESPONSES TO TUMOR-ASSOCIATED ANTIGENS E. Frederick Wheelock Department of Microbiology Je#erson Medical College Phil...
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