Targeting HIF-1α abrogates PD-L1-mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues.
Targeting HIF-1α abrogates PD-L1-mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues.
复制标题
靶向HIF-1α消除了肿瘤微环境中PD-L1介导的免疫逃避，但促进了正常组织中的耐受。
DOI：
10.1172/jci150846
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发表时间：
2022-05-02
影响因子：
15.9
通讯作者：
Wang, Yin
中科院分区：
文献类型：
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作者：
Bailey, Christopher M.;Liu, Yan;Liu, Mingyue;Du, Xuexiang;Devenport, Martin;Zheng, Pan;Liu, Yang;Wang, Yin
抗CTLA-4加抗PD-1/PD-L1的组合是最有效的癌症免疫疗法，但会导致免疫相关不良事件（irAE）的高发生率。在这里，我们报告了靶向HIF-1α抑制肿瘤细胞和肿瘤浸润性骨髓细胞上的PD-L1表达，但意外地通过IFN-γ依赖性机制诱导正常组织中的PD-L1。靶向肿瘤细胞中的HIF-1α/PD-L1轴可重新激活肿瘤浸润淋巴细胞并引起肿瘤排斥反应。HIF-1α抑制剂棘霉素增强了抗CTLA-4治疗的癌症免疫抑制作用，其疗效与抗CTLA-4加抗PD-1抗体相当。然而，虽然抗PD-1加重了易普利姆玛引发的irAE，但棘霉素通过增加正常组织中的PD-L1水平来保护小鼠免受irAE的影响。我们的数据表明，靶向HIF-1α可以增强PD-1/PD-L1检查点在正常组织中的免疫耐受功能，但可以消除其在肿瘤微环境中的免疫逃避功能，从而实现更安全，更有效的免疫治疗。
A combination of anti–CTLA-4 plus anti–PD-1/PD-L1 is the most effective cancer immunotherapy but causes high incidence of immune-related adverse events (irAEs). Here we report that targeting of HIF-1α suppressed PD-L1 expression on tumor cells and tumor-infiltrating myeloid cells, but unexpectedly induced PD-L1 in normal tissues by an IFN-γ–dependent mechanism. Targeting the HIF-1α/PD-L1 axis in tumor cells reactivated tumor-infiltrating lymphocytes and caused tumor rejection. The HIF-1α inhibitor echinomycin potentiated the cancer immunotherapeutic effects of anti–CTLA-4 therapy, with efficacy comparable to that of anti–CTLA-4 plus anti–PD-1 antibodies. However, while anti–PD-1 exacerbated irAEs triggered by ipilimumab, echinomycin protected mice against irAEs by increasing PD-L1 levels in normal tissues. Our data suggest that targeting HIF-1α fortifies the immune tolerance function of the PD-1/PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment to achieve safer and more effective immunotherapy.