Liu Kebin, Caldwell Sheila A, Greeneltch Kristy M, Yang Dafeng, Abrams Scott I
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bldg. 10, 10 Center Drive, Bethesda, MD 20892, USA.
J Immunol. 2006 Mar 15;176(6):3374-82. doi: 10.4049/jimmunol.176.6.3374.
Tumor escape and recurrence are major impediments for successful immunotherapy. It is well-documented that the emergence of Ag-loss variants, as well as regulatory mechanisms suppressing T cell function, have been linked to inadequate antitumor activity. However, little is known regarding the role of Fas-mediated cytotoxicity by tumor-specific CD8(+) CTL in causing immune evasion of Fas resistant variants during adoptive immunotherapy. In this study, we made use of an adoptive transfer model of experimental lung metastasis using tumor-specific CTL as a relevant immune-based selective pressure, and wherein the Fas ligand pathway was involved in the antitumor response. Surviving tumor cells were recovered and examined for alterations in antigenic, functional, and biologic properties. We showed that diminished susceptibility to Fas-mediated cytotoxicity in vivo was an important determinant of tumor escape following CTL-based immunotherapy. Tumor escape variants (TEV) recovered from the lungs of CTL-treated mice exhibited more aggressive behavior in vivo. However, these TEV retained relevant MHC class I and tumor Ag expression and sensitivity to CTL via the perforin pathway but reduced susceptibility to Fas-mediated lysis. Moreover, TEV were significantly less responsive to eradication by CTL adoptive immunotherapy paradigms as a consequence of increased Fas resistance. Overall, we identified that Fas(low)-TEV emerged as a direct consequence of CTL-tumor interactions in vivo, and that such an altered neoplastic Fas phenotype compromised immunotherapy efficacy. Together, these findings may have important implications for both tumor progression and the design of immunotherapeutic interventions to confront these selective pressures or escape mechanisms.
肿瘤逃逸和复发是免疫治疗成功的主要障碍。大量文献记载，抗原缺失变体的出现以及抑制T细胞功能的调节机制与抗肿瘤活性不足有关。然而，关于肿瘤特异性CD8(+)CTL通过Fas介导的细胞毒性在过继性免疫治疗期间导致Fas抗性变体免疫逃逸中的作用，人们了解甚少。在本研究中，我们利用了以肿瘤特异性CTL作为相关免疫选择性压力的实验性肺转移过继转移模型，其中Fas配体途径参与了抗肿瘤反应。回收存活的肿瘤细胞并检测其抗原性、功能性和生物学特性的改变。我们发现，体内对Fas介导的细胞毒性敏感性降低是基于CTL的免疫治疗后肿瘤逃逸的一个重要决定因素。从接受CTL治疗的小鼠肺部回收的肿瘤逃逸变体（TEV）在体内表现出更具侵袭性的行为。然而，这些TEV保留了相关的MHC I类和肿瘤抗原表达以及对通过穿孔素途径的CTL的敏感性，但对Fas介导的裂解的敏感性降低。此外，由于Fas抗性增加，TEV对CTL过继免疫治疗方案的根除反应明显降低。总体而言，我们确定Fas(低) - TEV是体内CTL与肿瘤相互作用的直接结果，并且这种肿瘤Fas表型的改变损害了免疫治疗效果。总之，这些发现可能对肿瘤进展以及对抗这些选择性压力或逃逸机制的免疫治疗干预设计具有重要意义。
