Patients with cancer with liver metastasis demonstrate significantly worse outcomes than those without liver metastasis when treated with anti–PD-1 immunotherapy. The mechanism of liver metastases–induced reduction in systemic antitumor immunity is unclear. Using a dual-tumor immunocompetent mouse model, we found that the immune response to tumor antigen presence within the liver led to the systemic suppression of antitumor immunity. The immune suppression was antigen specific and associated with the coordinated activation of regulatory T cells (T_regs) and modulation of intratumoral CD11b⁺ monocytes. The dysfunctional immune state could not be reversed by anti–PD-1 monotherapy unless T_reg cells were depleted (anti–CTLA-4) or destabilized (EZH2 inhibitor). Thus, this study provides a mechanistic understanding and rationale for adding T_reg and CD11b⁺ monocyte targeting agents in combination with anti–PD-1 to treat patients with cancer with liver metastasis.

当接受抗 PD-1 免疫疗法治疗时，患有肝转移的癌症患者的预后明显比没有肝转移的患者差。肝转移引起全身抗肿瘤免疫力降低的机制尚不清楚。使用双肿瘤免疫活性小鼠模型，我们发现肝脏内对肿瘤抗原存在的免疫反应导致抗肿瘤免疫的全身抑制。免疫抑制是抗原特异性的，并与调节性 T 细胞 (T _regs ) 的协调激活和瘤内 CD11b ⁺单核细胞的调节相关。功能失调的免疫状态无法通过抗 PD-1 单一疗法逆转，除非 T _reg细胞被耗尽（抗 CTLA-4）或不稳定（EZH2 抑制剂）。因此，这项研究为添加 T _reg和 CD11b ⁺单核细胞靶向药物联合抗 PD-1 治疗肝转移癌症患者提供了机制理解和基本原理。