Cytotoxins and cancer immunotherapy: the dance of the macabre?
Cytotoxins and cancer immunotherapy: the dance of the macabre?
复制标题
细胞毒素和癌症免疫疗法：可怕的舞蹈？
DOI：
10.1093/jnci/dji330
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Childs,RichardW
中科院分区：
文献类型：
--
作者：
Allegra,CarmenJ;Childs,RichardW
Carmen J. Allegra, Richard W. Childs this induction of TS protein along with its baseline relative overexpression in cancerous cells that provided the rationale for selecting this enzyme as a vaccine target. Overexpression of TS has also been shown to be associated with a poor prognosis in patients with colon and breast cancers and with relative insensitivity to 5-FU in patients with advanced disease (5, 6). Recently, it has been demonstrated that TS overexpression is oncogenic (7). Each of these features supports TS as a potential target for vaccination.Although in vitro and in vivo murine tumor models have provided us with tremendous insight into mechanisms to enhance antitumor immunity, relatively few humans have benefited from conventional peptide-based cancer immunotherapy. Bulky tumors outgrowing or suppressing the immune response, loss of the target antigen that is not essential for tumor survival, and poor host immunity as a consequence of immunosuppressive cytotoxic chemo/radiotherapy are all factors thought to play a role in the failure of peptide-based vaccination approaches. The ability to generate tumor antigen–specific immune responses in patients who ultimately do not achieve a disease response has led investigators to explore methods to sensitize the tumor to immune attack. Recently, radiotherapy and several cytotoxic agents have been shown to increase Fas and the expression of tumor-associated antigens such as carcinoembryonic antigen (CEA)(8). Although Correale et al. show that 5-FU sensitizes the tumor to killing by TS-specific CTL, definitive data showing that CTL killing is enhanced as a direct consequence of increased tumor surface expression of TS-derived peptide antigens are not presented in this study. An alternative explanation that needs to be considered is that the enhanced tumor susceptibility to T-cell attack is the result of another of the many cellular effects associated with exposure to 5-FU. Several laboratories have previously shown that 5-FU–exposed tumors increase the expression a variety of molecules including tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), Fas, and p53—molecules that might sensitize the tumor (and possibly nonmalignant cells) more globally to other antigen-specific CTL responses (9–11). A more comprehensive understanding of the mechanism of interaction may permit the use of more tumor-selective antigens and provide a broader menu of cytotoxic agents associated with increasing the expression of the critical molecule (s). Although alternative mechanisms that may underpin the noted synergy need further investigation, this fact does not detract from the importance of the present study.
