Melcher A, Todryk S, Hardwick N, Ford M, Jacobson M, Vile R G
Imperial Cancer Research Fund Laboratory of Molecular Therapy, ICRF Oncology Unit, Imperial College of Science and Medicine, Hammersmith Hospital, London, UK.
Nat Med. 1998 May;4(5):581-7. doi: 10.1038/nm0598-581.
In situ killing of tumor cells using suicide gene transfer to generate death by a non-apoptotic pathway was associated with high immunogenicity and induction of heat shock protein (hsp) expression. In contrast, a syngeneic colorectal tumor line, CMT93, killed predominantly by apoptosis, showed low levels of hsp expression and less immunogenicity. When apoptosis was inhibited in CMT93 cells by overexpression of bcl-2, hsp was also induced. Furthermore, when cDNA encoding hsp70 was stably transfected into B16 and CMT93 cells, its expression significantly enhanced the immunogenicity of both tumors. Increased levels of hsp, induced by non-apoptotic cell killing, may provide an immunostimulatory signal in vivo which helps break tolerance to tumor antigens. These findings have important implications for the development of novel anti-cancer therapies aimed at promoting patients' immune responses to their own tumors.
利用自杀基因转移通过非凋亡途径诱导肿瘤细胞原位死亡，与高免疫原性及热休克蛋白（hsp）表达的诱导相关。相比之下，一种主要通过凋亡途径杀伤的同基因结肠肿瘤细胞系CMT93，hsp表达水平较低且免疫原性较弱。当通过bcl-2过表达抑制CMT93细胞的凋亡时，hsp也被诱导。此外，当将编码hsp70的cDNA稳定转染至B16和CMT93细胞时，其表达显著增强了两种肿瘤的免疫原性。由非凋亡性细胞杀伤诱导的hsp水平升高，可能在体内提供一种免疫刺激信号，有助于打破对肿瘤抗原的耐受性。这些发现对于旨在促进患者对自身肿瘤产生免疫反应的新型抗癌疗法的开发具有重要意义。
