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Adoptive Transfer Enables Tumor Rejection Targeted against a Self-Antigen without the Induction of Autoimmunity¹

Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

We have previously described a tumor model in which the influenza hemagglutinin protein (HA) expressed on the BALB/c-derived MT901 tumor line serves as an immunization-dependent tumor rejection antigen in normal syngeneic mice. Although the HA antigen in this model is clearly foreign to normal BALB/c mice, many tumor antigens recognized by T cells in humans and mice are nonmutated antigens that are expressed on normal tissues as well as on the tumor cells, thereby raising issues of self-tolerance and autoimmunity in attempts to use such antigens therapeutically. To examine these issues, we have applied our tumor model to syngeneic mice that broadly express HA at low levels as a "self"-transgene. Unlike the situation in normal BALB/c mice, immunization of HA-transgenic mice did not result in tumor protection nor did it generate cytotoxic T cell or IgG responses against the HA self-antigen. However, if immunization of HA-transgenic mice was preceded by adoptive transfer of spleen and lymph node cells from normal untreated BALB/c mice, then HA-specific tumor protective immune responses were generated. Despite the self-nature of the HA antigen, no obvious manifestations of autoimmunity were observed. The immunity established in the transgenic mice was notably different from that observed in normal mice in that it was considerably more transient and required CD4 T cells for both successful immunization and subsequent tumor protection, qualities that were not associated with the immunity established in normal BALB/c mice. Collectively our results suggest that transferred cells can be transiently and selectively directed against a tumor-expressed self-antigen before returning to a tolerant state.

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