Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
PLoS One. 2012;7(4):e35222. doi: 10.1371/journal.pone.0035222. Epub 2012 Apr 6.
In prostate cancer, genes encoding androgen-regulated, Y-chromosome-encoded, and tissue-specific antigens may all be overexpressed. In the adult male host, however, most high affinity T cells targeting these potential tumor rejection antigens will be removed during negative selection. In contrast, the female mature T-cell repertoire should contain abundant precursors capable of recognizing these classes of prostate cancer antigens and mediating effective anti-tumor immune responses.
METHODOLOGY/PRINCIPAL FINDINGS: We find that syngeneic TRAMP-C2 prostatic adenocarcinoma cells are spontaneously rejected in female hosts. Adoptive transfer of naïve female lymphocytes to irradiated male hosts bearing pre-implanted TRAMP-C2 tumor cells slows tumor growth and mediates tumor rejection in some animals. The success of this adoptive transfer was dependent on the transfer of female CD4 T cells and independent of the presence of CD25-expressing regulatory T cells in the transferred lymphocytes. We identify in female CD4 T cells stimulated with TRAMP-C2 a dominant MHC II-restricted response to the Y-chromosome antigen DBY. Furthermore, CD8 T cell responses in female lymphocytes to the immunodominant MHC I-restricted antigen SPAS-1 are markedly increased compared to male mice. Finally, we find no exacerbation of graft-versus-host disease in either syngeneic or minor-antigen mismatched allogeneic lymphocyte adoptive transfer models by using female into male versus male into male cells.
CONCLUSIONS/SIGNIFICANCE: This study shows that adoptively transferred female lymphocytes, particularly CD4 T cells, can control the outgrowth of pre-implanted prostatic adenocarcinoma cells. This approach does not significantly worsen graft-versus-host responses suggesting it may be viable in the clinic. Further, enhancing the available immune repertoire with female-derived T cells may provide an excellent pool of prostate cancer reactive T cells for further augmentation by combination with either vaccination or immune regulatory blockade strategies.
在前列腺癌中，编码雄激素调节、Y 染色体编码和组织特异性抗原的基因可能都过度表达。然而，在成年雄性宿主中，大多数针对这些潜在肿瘤排斥抗原的高亲和力 T 细胞将在阴性选择过程中被清除。相比之下，女性成熟 T 细胞库应该包含丰富的前体细胞，能够识别这些前列腺癌抗原类别并介导有效的抗肿瘤免疫反应。
方法/主要发现：我们发现，同基因 TRAMP-C2 前列腺腺癌细胞在雌性宿主中自发被排斥。将幼稚的雌性淋巴细胞过继转移到接受过辐照的雄性宿主中，这些雄性宿主带有预先植入的 TRAMP-C2 肿瘤细胞，可以减缓肿瘤生长并在一些动物中介导肿瘤排斥。这种过继转移的成功依赖于雌性 CD4 T 细胞的转移，并且与转移淋巴细胞中是否存在表达 CD25 的调节性 T 细胞无关。我们在刺激 TRAMP-C2 的雌性 CD4 T 细胞中鉴定出一种对 Y 染色体抗原 DBY 的主要 MHC II 限制性反应。此外，与雄性小鼠相比，雌性淋巴细胞对免疫显性 MHC I 限制性抗原 SPAS-1 的 CD8 T 细胞反应明显增加。最后，我们发现，无论是在同基因还是在次要抗原不匹配的同种异体淋巴细胞过继转移模型中，使用雌性到雄性而非雄性到雄性的细胞，都不会加重移植物抗宿主病。
结论/意义：本研究表明，过继转移的雌性淋巴细胞，特别是 CD4 T 细胞，可以控制预先植入的前列腺腺癌细胞的生长。这种方法不会显著加重移植物抗宿主反应，表明它在临床上可能是可行的。此外，通过使用雌性来源的 T 细胞增强可用的免疫库，可以为进一步增强提供一个极好的前列腺癌反应性 T 细胞库，与疫苗接种或免疫调节阻断策略相结合。
