Rationale: Multiple copies in T-cell malignancy 1 (MCT-1) is a prognostic biomarker for aggressive breast cancers. Overexpressed MCT-1 stimulates the IL-6/IL-6R/gp130/STAT3 axis, which promotes epithelial-to-mesenchymal transition and cancer stemness. Because cancer stemness largely contributes to the tumor metastasis and recurrence, we aimed to identify whether the blockade of MCT-1 and IL-6R can render these effects and to understand the underlying mechanisms that govern the process./nMethods: We assessed primary tumor invasion, postsurgical local recurrence and distant metastasis in orthotopic syngeneic mice given the indicated immunotherapy and MCT-1 silencing (shMCT-1)./nResults: We found that shMCT-1 suppresses the transcriptomes of the inflammatory response and metastatic signaling in TNBC cells and inhibits tumor recurrence, metastasis and mortality in xenograft mice. IL-6R immunotherapy and shMCT-1 combined further decreased intratumoral M2 macrophages and T regulatory cells (Tregs) and avoided postsurgical TNBC expansion. shMCT-1 also enhances IL-6R-based immunotherapy effectively in preventing postsurgical TNBC metastasis, recurrence and mortality. Anti-IL-6R improved helper T, cytotoxic T and natural killer (NK) cells in the lymphatic system and decreased Tregs in the recurrent and metastatic tumors. Combined IL-6R and PD-L1 immunotherapies abridged TNBC cell stemness and M2 macrophage activity to a greater extent than monotherapy. Sequential immunotherapy of PD-L1 and IL-6R demonstrated the best survival outcome and lowest postoperative recurrence and metastasis compared with synchronized therapy, particularly in the shMCT-1 context. Multiple positive feedforward loops of the MCT-1/IL-6/IL-6R/CXCL7/PD-L1 axis were identified in TNBC cells, which boosted metastatic niches and immunosuppressive microenvironments. Clinically, MCT-1^high/PD-L1^high/CXCL7^high and CXCL7^high/IL-6^high/IL-6R^high expression patterns predict worse prognosis and poorer survival of breast cancer patients./nConclusion: Systemic targeting the MCT-1/IL-6/IL-6R/CXCL7/PD-L1 interconnections enhances immune surveillance that inhibits the aggressiveness of TNBC.

中文翻译：

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免疫治疗 IL-6R 和靶向 MCT-1/IL-6/CXCL7/PD-L1 回路可预防三阴性乳腺癌的复发和转移

理由： T 细胞恶性肿瘤 1 (MCT-1) 中的多拷贝是侵袭性乳腺癌的预后生物标志物。过度表达的 MCT-1 会刺激 IL-6/IL-6R/gp130/STAT3 轴，从而促进上皮间质转化和癌症干性。由于癌症干性在很大程度上导致肿瘤转移和复发，因此我们旨在确定 MCT-1 和 IL-6R 的阻断是否可以产生这些影响，并了解控制该过程的潜在机制。/n方法：我们评估了原发性肿瘤给予指定免疫治疗和 MCT-1 沉默 (shMCT-1) 的原位同系小鼠中的侵袭、术后局部复发和远处转移。/n结果：我们发现 shMCT-1 抑制 TNBC 细胞中炎症反应和转移信号的转录组并抑制异种移植小鼠的肿瘤复发、转移和死亡率。 IL-6R 免疫疗法和 shMCT-1 相结合，进一步减少瘤内 M2 巨噬细胞和 T 调节细胞 (Treg)，并避免术后 TNBC 扩增。 shMCT-1还可以增强基于IL-6R的免疫疗法，有效预防术后TNBC转移、复发和死亡。抗IL-6R可改善淋巴系统中的辅助性T细胞、细胞毒性T细胞和自然杀伤(NK)细胞，并减少复发性和转移性肿瘤中的Treg细胞。 IL-6R 和 PD-L1 联合免疫疗法比单一疗法更大程度地降低了 TNBC 细胞干性和 M2 巨噬细胞活性。与同步治疗相比，PD-L1 和 IL-6R 的序贯免疫治疗显示出最佳的生存结果以及最低的术后复发和转移，特别是在 shMCT-1 背景下。在 TNBC 细胞中发现了 MCT-1/IL-6/IL-6R/CXCL7/PD-L1 轴的多个正前馈环，这增强了转移微环境和免疫抑制微环境。临床上，MCT-1^高/PD-L1^高/CXCL7^高和CXCL7^高/IL-6^高/IL-6R^高表达模式预示乳腺癌患者预后较差，生存率较差。 /n结论：系统性靶向 MCT-1/IL-6/IL-6R/CXCL7/PD-L1 互连可增强免疫监视，从而抑制 TNBC 的侵袭性。