Benslimane Yasmine, Amalfi Kevin, Lapin Sara, Perrino Stephanie, Brodt Pnina
Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Canada.
The Research Institute of the McGill University Health Center, Montreal, Canada.
Cancer Res Commun. 2024 Aug 1;4(8):1963-1977. doi: 10.1158/2767-9764.CRC-24-0196.
Liver metastases (LM) remain a major cause of cancer-related death and are a major clinical challenge. LM and the female sex are predictors of a poorer response to immunotherapy but the underlying mechanisms remain unclear. We previously reported on a sexual dimorphism in the control of the tumor microenvironment (TME) of colorectal carcinoma liver metastases (CRCLM) and identified estrogen as a regulator of an immunosuppressive TME in the liver. Here we aimed to assess the effect of estrogen deprivation on the cytokine/chemokine profile associated with CRCLM, using a multiplex cytokine array and the RNAscope technology, and its effects on the innate and adaptive immune responses in the liver. We also evaluated the benefit of combining the selective estrogen-receptor degrader Fulvestrant with immune checkpoint blockade for the treatment of CRCLM. We show that estrogen depletion altered the cytokine/chemokine repertoire of the liver, decreased macrophage polarization, as reflected in reduced accumulation of tumor infiltrating M2 macrophages and increased the accumulation of CCL5+/CCR5+ CD8+ T and NKT cells in the liver TME. Similar results were obtained in a murine pancreatic ductal adenocarcinoma model. Importantly, treatment with Fulvestrant also increased the accumulation of CD8+CCL5+, CD8+CCR5+ T and NK cells in the liver TME and enhanced the therapeutic benefit of anti-PD1 immunotherapy, resulting in a significant reduction in the outgrowth of LM. Taken together, our results show that estrogen regulates immune cell recruitment to the liver and suggest that inhibition of estrogen action could potentiate the tumor-inhibitory effect of immunotherapy in hormone-independent and immunotherapy-resistant metastatic cancer.
The immune microenvironment of the liver plays a major role in controlling the expansion of hepatic metastases and is regulated by estrogen. We show that treatment of tumor-bearing mice with an estrogen receptor degrader potentiated an anti-metastatic effect of immunotherapy. Our results provide mechanistic insight into clinical findings and a rationale for evaluating the efficacy of combination anti-estrogen and immunotherapy for prevention and/or treatment of hepatic metastases in female patients.
肝转移（LM）仍然是癌症相关死亡的主要原因，也是一项重大的临床挑战。肝转移和女性性别是免疫治疗反应较差的预测因素，但其潜在机制仍不清楚。我们之前报道了结直肠癌肝转移（CRCLM）的肿瘤微环境（TME）控制中存在性别差异，并确定雌激素是肝脏中免疫抑制性TME的调节因子。在此，我们旨在使用多重细胞因子阵列和RNAscope技术评估雌激素剥夺对与CRCLM相关的细胞因子/趋化因子谱的影响，及其对肝脏先天和适应性免疫反应的影响。我们还评估了将选择性雌激素受体降解剂氟维司群与免疫检查点阻断联合用于治疗CRCLM的益处。我们发现，雌激素耗竭改变了肝脏的细胞因子/趋化因子库，减少了巨噬细胞极化，这表现为肿瘤浸润性M2巨噬细胞的积累减少，并增加了肝脏TME中CCL5+/CCR5+ CD8+ T细胞和NKT细胞的积累。在小鼠胰腺导管腺癌模型中也获得了类似的结果。重要的是，氟维司群治疗还增加了肝脏TME中CD8+CCL5+、CD8+CCR5+ T细胞和NK细胞的积累，并增强了抗PD1免疫治疗的疗效，导致肝转移的生长显著减少。综上所述，我们的结果表明雌激素调节免疫细胞向肝脏的募集，并表明抑制雌激素作用可增强免疫疗法在激素非依赖性和免疫疗法抗性转移性癌症中的肿瘤抑制作用。
肝脏的免疫微环境在控制肝转移的扩展中起主要作用，并受雌激素调节。我们表明，用雌激素受体降解剂治疗荷瘤小鼠可增强免疫疗法的抗转移作用。我们的结果为临床发现提供了机制性见解，并为评估联合抗雌激素和免疫疗法预防和/或治疗女性患者肝转移的疗效提供了理论依据。
