Interferon gamma and tumor necrosis factor have a role in tumor regressions mediated by murine CD8+ tumor-infiltrating lymphocytes.

Abstract

SummaryWe have investigated the mechanisms whereby adoptively transferred murine CD8+ lymphocytes mediate tumor regressions. Noncytolytic, CD8+ tumor-infiltrating lymphocytes (TIL) eradicated established lung tumors in irradiated mice. Many cytolytic and noncytolytic CD8+ TIL cultures specifically secreted interferon y (IFN-y) and tumor necrosis factor when stimulated with tumor cells in vitro. The effectiveness ofTIL when adoptively transferred to micebearing micrometastases correlated better with their ability to specifically secrete lymphokines than with their cytotoxicity in vitro. In 14 of 15 tests, therapeutically effective TIL specifically secreted IFN-y in vitro, whereas only 1 of 11 ineffective TIL specifically secreted IFN-y . In contrast, only 8 of 15 therapeutically effective TIL were cytolytic. Antibodies to TNF inhibited the effectiveness of two adoptively transferred TIL cultures . In five experiments, antibodies to IFN-y abrogated the ability of four different CD8 + TIL cultures to mediate tumor regressions, indicating that secretion of IFN-y is an essential part of the mechanism of action of TIL.arly studies in mice investigating the mechanisms involved in syngeneic tumor regressions mediated by the transfer of T lymphocytes found a strong correlation between tests ofin vitro cytotoxicity and in vivo antitumor effect (1-6). This correlation suggested that T cells with in vitro cytotoxicity were involved in tumor rejection in vivo and that the mechanism of rejection was direct cytolysis . However, the availability of mAbs to distinguish murine helper CD4+ and cytolytic CD8+ lymphocytes enabled investigators to deplete one or the other T cell subset and test each for their ability to cause tumor regressions in vivo. When cytolytic CD8+ lymphocytes were depleted, the resultant noncytolytic CD4+ lymphocytes were as capable as the nondepleted culture in eliciting rejection or preventing the outgrowth of leukemias (7), virally induced sarcomas (8), chemically induced sarcomas (9), and plasmacytomas (10) in murine models .The possibility that these helper CD4+ cells were activating host cytolytic CD8+ lymphocytes to mediate tumor regression was investigated by using mice that were thymectomized, lethally irradiated, and then reconstituted with T cell-depleted, syngeneic bone marrow (B mice) . The adoptive transfer of C138-depleted splenocytes from tumor-immune mice to such B mice still eradicated the established tumor (11) and prevented the outgrowth ofa subsequent tumor challenge (10). Although no cells that were cytotoxic to tumor could be cultured from the splenocytes of these cured mice, they were able to mediate a tumor-specific, delayed-type hyper-647 sensitivity (DTH)t reaction when re-challenged with a tumor. These observations led investigators to propose that CD4+ lymphocytes may convey tumor resistanceby initiating a DTH reaction at the tumor site, thus implicating macrophages, the cytotoxic cells in DTH reactions, as the final effectors oftumor killing. Further support for this hypothesis c...

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