免疫检查点阻断（ICB）在晚期癌症患者中的临床成功最近推动了ICB在新辅助和围手术期实施的临床应用。然而，新辅助ICB疗法如何影响全身免疫景观和转移扩散尚未确定。肿瘤促进调节性T细胞（Treg）的局部和全身扩增，它们是肿瘤诱导的免疫抑制的关键组织者，为免疫逃逸、肿瘤进展和转移做出了贡献。Treg表达抑制性免疫检查点分子，因此可能是ICB疗法的意外靶点，从而抵消其疗效。在反应不良的ICB模型中，重现了乳腺癌患者ICB反应较弱的原发性和转移性乳腺癌，我们观察到联合抗PD-1和抗CTLA-4疗法不经意地促进了肿瘤、肿瘤引流淋巴结和循环中Treg的增殖和活化。在乳腺癌患者中，ICB后Treg水平升高。在肿瘤携带小鼠中消灭Treg不仅重新塑造了肿瘤内免疫景观，使之对ICB疗效更有利，还诱导了系统免疫的深刻和持久的改变，特征为升高的CD8+ T细胞和NK细胞以及可持续的T细胞激活，治疗停药后维持下来。虽然Treg的消减和新辅助ICB疗法的结合不能抑制原发性肿瘤的生长，但它延长了转移相关的生存，主要由CD8+ T细胞驱动。本研究表明，乳腺癌的新辅助ICB疗法可以通过同时靶向Treg来增强治疗效果，延长转移相关的生存，独立于原发性肿瘤的反应。©2023年作者。使用Taylor＆Francis Group，LLC许可证进行发布。

The clinical successes of immune checkpoint blockade (ICB) in advanced cancer patients have recently spurred the clinical implementation of ICB in the neoadjuvant and perioperative setting. However, how neoadjuvant ICB therapy affects the systemic immune landscape and metastatic spread remains to be established. Tumors promote both local and systemic expansion of regulatory T cells (Tregs), which are key orchestrators of tumor-induced immunosuppression, contributing to immune evasion, tumor progression and metastasis. Tregs express inhibitory immune checkpoint molecules and thus may be unintended targets for ICB therapy counteracting its efficacy. Using ICB-refractory models of spontaneous primary and metastatic breast cancer that recapitulate the poor ICB response of breast cancer patients, we observed that combined anti-PD-1 and anti-CTLA-4 therapy inadvertently promotes proliferation and activation of Tregs in the tumor, tumor-draining lymph node and circulation. Also in breast cancer patients, Treg levels were elevated upon ICB. Depletion of Tregs during neoadjuvant ICB in tumor-bearing mice not only reshaped the intratumoral immune landscape into a state favorable for ICB response but also induced profound and persistent alterations in systemic immunity, characterized by elevated CD8+ T cells and NK cells and durable T cell activation that was maintained after treatment cessation. While depletion of Tregs in combination with neoadjuvant ICB did not inhibit primary tumor growth, it prolonged metastasis-related survival driven predominantly by CD8+ T cells. This study demonstrates that neoadjuvant ICB therapy of breast cancer can be empowered by simultaneous targeting of Tregs, extending metastasis-related survival, independent of a primary tumor response.© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.