大家好， 笔者最近看到Nature Communication上新发的一篇有关癌症免疫治疗的文章，借助BioEngX平台跟大家分享一下。这篇文章的题目是“Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints.”文章通讯作者为哈佛大学的Glenn Dranoff。据该文章报道，癌症治疗过程中对抗PD-1抗体治疗出现抵抗或与其他癌症免疫检查点上调有关。
目前PD-1/PD-L1是被研究最多的癌症检查点，通过抗PD-1抗体阻断该检查点已被广泛证实对多种肿瘤治疗均有效。抗PD-1抗体通过结合于效应T细胞的PD-1受体上阻断PD-1 与肿瘤细胞表面的PD-L1配体结合，阻断效应T细胞被肿瘤细胞诱导凋亡，从而保留住可以抵抗肿瘤的T细胞。但临床上经过几个疗程抗PD-1抗体治疗后病人还是难免会出现治疗抵抗及病情进展。
在该研究中，作者通过突变KRAS或EGFR两个基因构建了两种小鼠肺腺癌模型。然后在未来8-10周用相同剂量的抗PD-1抗体给与小鼠治疗。作者发现经过一周抗PD-1抗体治疗后，小鼠CD4T细胞及CD8T细胞的TIM-3的表达量明显上调且呈现明显时间依赖性。此外，T细胞群体中能与抗PD-1抗体结合的T细胞数量也与TIM-3的表达量呈现相关性。
抗PD-1抗体治疗小鼠癌症模型方案
抗PD-1抗体治疗上调T细胞TIM-3的表达
接下来作者选择了对抗PD-1抗体治疗反应较好的EGFR突变模型小鼠用于后续试验。在小鼠对抗PD-1抗体治疗出现抵抗肿瘤发生进展时，作者紧接着给与小鼠模型抗TIM-3抗体治疗。作者发现相比于只给与抗PD-1抗体的小鼠，两种抗体顺序联用的小鼠中位生存期由5周延长到约12周。
抗PD-1抗体与抗TIM-3抗体联合治疗方案及效果
为了验证在小鼠模型中的发现是否与临床上病人出现的PD-1抗体治疗抵抗有关联，作者分析了两位经过抗PD-1抗体治疗过的病人的样本。两位病人分别经过四个月及五个月的抗PD-1抗体治疗后出现病情进展，通过对血液中的T细胞进行分析发现出现治疗抵抗后仍有约一半的CD4和CD8 T细胞表达PD-1，但是与其他未经过抗PD-1抗体治疗的病人相比，这两个病人T细胞TIM-3的表达量明显偏高。这也与在小鼠肿瘤模型中的发现遥相呼应。
与抗PD-1抗体研发的如火如荼相比，抗TIM-3抗体的研发相对较冷门。根据笔者所知，目前只有美国的TESARO制药公司刚刚提交TIM-3抗体的临床申请。NC上这篇报道或许会对TIM-3抗体或PD-1/TIM-3双特异抗体的临床应用起到促进作用。
由于篇幅限制，笔者只对该文章做了简短解读，如想深入了解该研究大家可去细品此文。
BioEngX官方作者：王宝龙，伦敦大学学院生化工程系博士
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