LeGrue S J, Ananthaswamy H N, Simcik W J
Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Cancer Res. 1989 Sep 1;49(17):4747-51.
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.
高免疫原性（Imm+）的小鼠肿瘤细胞变体能够引发强烈的肿瘤特异性交叉保护免疫反应，以抵御弱免疫原性亲代肿瘤细胞系的攻击。我们研究了用小鼠纤维肉瘤MCA-F的Imm+变体（命名为MCA-FM1）免疫后观察到的亲代交叉保护免疫的传入诱导和传出特异性。通过用肿瘤MCA-D攻击来监测用MCA-FM1变体免疫的小鼠中针对亲代肿瘤的传入和传出反应的特异性，MCA-D表达一种肿瘤特异性抗原，该抗原在免疫学上与MCA-F抗原不同，但在生化上相关。我们观察到，免疫时MCA-D和MCA-FM1细胞的混合物未能引发针对MCA-D攻击的强烈肿瘤排斥反应。用MCA-FM1和MCA-D细胞的混合物攻击MCA-FM1免疫的小鼠，在Imm+排斥部位产生了显著的旁观者效应，MCA-D肿瘤的生长受到抑制。为了验证亲代交叉保护免疫的诱导需要在同一细胞上同时识别Imm+新抗原和亲代肿瘤抗原这一假设，我们构建了MCA-D与MCA-F或MCA-FM1的体细胞杂种。令人惊讶的是，杂种细胞不表达融合亲本上存在的任何一种亲代肿瘤特异性抗原，而是表现出一种独特的抗原特异性，命名为F/D。免疫原性和非免疫原性杂种细胞系均表达F/D抗原，表明肿瘤特异性F/D抗原是交叉保护免疫的焦点。这些结果表明，肿瘤特异性亲代抗原与Imm+变体表面共表达的强免疫原性新抗原的联合识别负责抗亲代交叉保护免疫的传入诱导和传出激发。此外，本研究首次报道，两种同基因肿瘤细胞系的融合可重复性地产生一种新的肿瘤抗原特异性，而牺牲了原来的亲代特异性。
