Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints.
Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints.
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DOI：
10.1038/ncomms10501
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发表时间：
2016-02-17
影响因子：
16.6
通讯作者：
Hammerman PS
中科院分区：
文献类型：
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作者：
Koyama S;Akbay EA;Li YY;Herter-Sprie GS;Buczkowski KA;Richards WG;Gandhi L;Redig AJ;Rodig SJ;Asahina H;Jones RE;Kulkarni MM;Kuraguchi M;Palakurthi S;Fecci PE;Johnson BE;Janne PA;Engelman JA;Gangadharan SP;Costa DB;Freeman GJ;Bueno R;Hodi FS;Dranoff G;Wong KK;Hammerman PS
尽管针对程序死亡1（PD-1）的抗体的抗肿瘤活性令人信服：肺癌中编程的死亡配体1（PD-L1）免疫检查点，越来越多地观察到对这些疗法的耐药性。在这项研究中，为了阐明自适应抗性的机制，我们在两种完全免疫能力的肺腺癌小鼠模型中分析了抗PD-1治疗的肿瘤微环境。在反应抗PD-1治疗后的肿瘤中，我们观察到替代免疫检查点的上调，尤其是在PD-1抗体结合的T细胞中，尤其是T细胞免疫球蛋白粘蛋白-3（TIM-3） PD-1封锁失败后的TIM-3阻断抗体的。两名患者对抗PD-1治疗的自适应性也显示出在治疗失败时阻断抗体结合的T细胞的TIM-3上调。这些数据表明，TIM-3和其他免疫检查点的上调可能是与PD-1阻滞性适应性抗性相关的可定位生物标志物。
阻止免疫检查点是治疗肺癌的有前途的策略，但患者经常对治疗具有抵抗力。在这里，作者分析了肺癌小鼠模型中的耐药性，并显示了小鼠和两名患者的抗性，TIM3的表达增加，这也参与了对癌症的免疫反应。
Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade. Blocking immune checkpoints is a promising strategy to treat lung cancer, but patients often become resistant to the therapy. Here, the authors analyse resistance in mouse models of lung cancer and show in mice and two patients, an increase in the expression of TIM3, which is also involved in the immune response to cancer.