肿瘤相关中性粒细胞通过招募Foxp3+调节性T细胞促进肝癌对PD-1抗体耐药的机制及其干预

最近两项针对肝癌的PD-1抗体III期临床试验均以失败而告终，因此找到PD-1抗体在肝癌中的耐药机制将成为当下肝癌研究的迫切任务。本研究前期构建了小鼠PD-1抗体耐药原位肝癌模型，我们通过细胞因子芯片发现PD-1抗体耐药肿瘤中的CXCL5和VEGFA明显上调，同时我们进一步分析发现耐药肿瘤的中性粒细胞和Foxp3+调节性T细胞（Treg）明显增多，动物试验验证了中性粒细胞抗体与PD-1抗体联合治疗可以消除肝癌对PD-1抗体的耐药。因此，我们提出具体机制假设：肝癌细胞通过分泌CXCL5和VEGFA招募并激活中性粒细胞，中性粒细胞通过招募Foxp3+Treg降低杀伤性T细胞的功能，最后导致肝癌细胞对免疫检查点治疗耐药。如果上述假想成立，通过抗PD-1抗体联合中性粒细胞抗体或anti-VEGFA抗体有望消除PD-1抗体在肝癌中的耐药，为肝癌患者提供一个全新的治疗方案。

Recently two phase III clinical trials of anti-PD-1 antibody have failed in Hepatocellular carcinoma（HCC）. Therefore, it will be urgently needed to identify the molecular mechanism of PD-1 antibody resistance and improving the efficacy of PD-1 antibody in HCC. In this study, we constructed the PD-1 antibody resistance model in orthotopic HCC mice and found that CXCL5 and VEGFA were significantly upregulated in anti-PD-1 resistant tumor. Meanwhile, immunohistochemistry and flow cytometry analysis showed that neutrophils and Foxp3+ regulatory T cells were dramatically increased in anti-PD-1 resistant tumor. Animal experiments demonstrated that neutrophils antibody combined with anti-PD-1 antibody treatment eliminated PD-1 antibody resistance in HCC. Therefore, we hypothesize that CXCL5 and VEGFA secreted by resistant HCC cells can recruit and activate neutrophils respectively to further recruit Foxp3+ Treg cells, finally influencing the cytotoxicity T lymphocyte function and induce resistance to checkpoints treatment. If the above hypothesis can be confirmed, the combination of anti-PD-1 antibody with anti-neutrophil or anti-VEGFA antibody are expected to eliminate the PD-1 antibody resistance in HCC and will provide a new therapeutic strategy for HCC patients.