Ioannides C G, Whiteside T L
Department of Gynecology, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
Clin Immunol Immunopathol. 1993 Feb;66(2):91-106. doi: 10.1006/clin.1993.1012.
Based on experimental and clinical data, it appears that human T cells are capable of mediating tumor cell destruction and, thus, are potentially important for immunotherapy of cancer. To date, neither the mechanisms responsible for T cell-mediated tumor cell destruction in vivo nor in vitro correlates of clinical responses in cancer patients treated with immunotherapy have been defined. Nevertheless, substantial evidence for the presence in cancer patients of specific autotumor (AuTu) responses mediated by T lymphocytes has accumulated. T cells recognize tumor-associated antigens (Ags) by means of clonally distributed T cell receptors (TCR). Molecular analysis of the preferential use of the TCR V beta gene families for recognition of Ags (tumor-associated peptides) by circulating or tumor-infiltrating T cells indicates that clones of AuTu-reactive effector T cells are present in patients with cancer. Recent advances in the characterization of tumor peptides bound to the MHC class I or class II molecules, definition of allele-specific consensus motifs, and availability of computer programs for modeling of T cell Ag interactions now allow for identification of specific T cell-reactive tumor peptide epitopes from proteins with known amino acid sequences. Also, the tumor-bearing host appears to be able to discriminate between tolerance to self, antitumor responses, and autoimmune phenomena. This type of a regulatory mechanism has not been precisely defined, but it might be surmised that immunosuppression, which is commonly seen in the tumor microenvironment, may result from attempts by the host to dampen or control self-reactivity rather than from tumor-induced down-regulation of T cell responses to escape immune surveillance. To progress toward molecular immunotherapy of cancer and to overcome tumor-host-induced immunosuppression in the tumor microenvironment, a better understanding of T cell-tumor interactions is necessary. It might be possible in the future to select for therapy clones of human T cells expressing the desired TCR and reacting with specific tumor peptides. It might also be feasible to reduce or eliminate tumor-mediated immunosuppression of T cell responses. Such selective molecular interventions in human cancers will depend on current advances in the definition of tumor Ag epitopes which elicit strong and sustained T cell responses.
基于实验和临床数据，人类T细胞似乎能够介导肿瘤细胞的破坏，因此，对于癌症的免疫治疗具有潜在的重要意义。迄今为止，体内T细胞介导肿瘤细胞破坏的机制以及接受免疫治疗的癌症患者临床反应的体外相关因素均未明确。然而，已有大量证据表明癌症患者体内存在由T淋巴细胞介导的特异性自身肿瘤（AuTu）反应。T细胞通过克隆分布的T细胞受体（TCR）识别肿瘤相关抗原（Ag）。对循环或肿瘤浸润T细胞识别抗原（肿瘤相关肽）时TCR Vβ基因家族优先使用情况的分子分析表明，癌症患者体内存在AuTu反应性效应T细胞克隆。近期在与MHC I类或II类分子结合的肿瘤肽表征、等位基因特异性共有基序的定义以及T细胞Ag相互作用建模计算机程序可用性方面的进展，现在使得能够从具有已知氨基酸序列的蛋白质中鉴定出特定的T细胞反应性肿瘤肽表位。此外，荷瘤宿主似乎能够区分对自身的耐受、抗肿瘤反应和自身免疫现象。这种调节机制尚未精确界定，但可以推测，肿瘤微环境中常见的免疫抑制可能是宿主试图抑制或控制自身反应性的结果，而非肿瘤诱导T细胞反应下调以逃避免疫监视。为了在癌症分子免疫治疗方面取得进展并克服肿瘤微环境中肿瘤-宿主诱导的免疫抑制，有必要更好地理解T细胞与肿瘤的相互作用。未来有可能选择表达所需TCR并与特定肿瘤肽反应的人类T细胞克隆进行治疗。减少或消除肿瘤介导的T细胞反应免疫抑制也可能是可行的。这种对人类癌症的选择性分子干预将取决于目前在定义能引发强烈且持续T细胞反应的肿瘤Ag表位方面的进展。
