Highly immunogenic (Imm+) murine tumor cell variants can engender a strong tumor-specific, cross-protective immune response against challenge with the weakly immunogenic parental tumor cell line. We examined the afferent induction and efferent specificity of the parental cross-protective immunity observed following immunization with the Imm+ variant of the murine fibrosarcoma MCA-F, designated MCA-FM1. Specificity of the afferent and efferent responses against the parental tumor in mice immunized with the MCA-FM1 variant were monitored by challenge with the tumor MCA-D, which expresses a tumor-specific antigen that is immunologically distinct from but biochemically related to the MCA-F antigen. We observed that mixture of MCA-D and MCA-FM1 cells at immunization failed to elicit a strong tumor rejection response against challenge with MCA-D. Challenge of MCA-FM1-immune mice with a mixture of MCA-FM1 and MCA-D cells resulted in a significant bystander effect at the site of Imm+ rejection, with reduced growth of the MCA-D tumor. To test the hypothesis that the induction of parental cross-protective immunity required the associative recognition of both the Imm+ neoantigen and the parental tumor antigen on the same cell, we constructed somatic cell hybrids of MCA-D with either MCA-F or MCA-FM1. Surprisingly, the hybrids did not express either parental tumor-specific antigen present on the fusion partners but displayed a unique antigenic specificity designated F/D. Expression of the F/D antigen by both the immunogenic and nonimmunogenic hybrid cell lines demonstrated that the tumor-specific F/D antigen was the focus of the cross-protective immunity. These results demonstrate that associative recognition of the tumor-specific parental antigen with the strongly immunogenic neoantigen coexpressed on the surface of the Imm+ variant is responsible for the afferent induction and efferent elicitation of anti-parental cross-protective immunity. Furthermore, this study is the first to report that the fusion of two syngeneic tumor cell lines reproducibly results in a new tumor antigen specificity at the expense of the original parental specificities.

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Supported by Grant RR-5511-23 awarded by the National Cancer Institute and by The University of Texas Cancer Foundation.

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