Hargrove-Wiley Ebony, Obodo Dora, Bindeman Wendy, Fingleton Barbara
Program in Cancer Biology, Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Int J Mol Sci. 2024 Dec 6;25(23):13113. doi: 10.3390/ijms252313113.
Breast cancer is commonly thought of as a "women's disease". However, men are increasingly diagnosed with the disease, and their mortality rates are disparately higher than those of female patients. The abundance and composition of the immune microenvironment are determinants of breast cancer progression and survival. It is well documented that there are sex-specific differences in the immune response to several diseases, including various cancers. However, the effects of these differences in the context of breast cancer remain to be explored. This study demonstrates sex differences in the hormonal and immune landscape of the MMTV-PyMT transgenic murine model of female and male ER+ breast cancer using single-cell RNA sequencing (scRNA-Seq), whole-slide immunohistochemistry, and flow cytometry. Mammary tumors of transgenic male mice had increased estrogen receptor alpha expression and enriched nuclear binding signatures compared to female tumors. In the tumor immune compartment, male mice had lower intratumoral leukocyte infiltration. Yet, scRNA-Seq analysis reveals a more immunostimulatory microenvironment and increased antitumor immune populations in the primary and metastatic lungs as compared to transgenic females. Despite a more favorable innate immune profile, the metastatic burden was increased in male mice. Our data support a sex-dependent immune response in mammary carcinoma associated with the tumor, and likely host, hormonal environment. With emerging therapeutics targeting the tumor immune microenvironment, characterizing immune profiles is critical for optimizing their use in all breast cancer patients.
乳腺癌通常被认为是一种“女性疾病”。然而，越来越多的男性被诊断出患有这种疾病，而且他们的死亡率明显高于女性患者。免疫微环境的丰度和组成是乳腺癌进展和生存的决定因素。有充分的文献记载，在对包括各种癌症在内的几种疾病的免疫反应中存在性别特异性差异。然而，这些差异在乳腺癌背景下的影响仍有待探索。本研究使用单细胞RNA测序（scRNA-Seq）、全切片免疫组织化学和流式细胞术，展示了雌性和雄性ER+乳腺癌的MMTV-PyMT转基因小鼠模型在激素和免疫格局方面的性别差异。与雌性肿瘤相比，转基因雄性小鼠的乳腺肿瘤雌激素受体α表达增加，核结合特征富集。在肿瘤免疫区室中，雄性小鼠的肿瘤内白细胞浸润较少。然而，scRNA-Seq分析显示，与转基因雌性小鼠相比，原发性和转移性肺中的免疫刺激微环境更强，抗肿瘤免疫细胞群增加。尽管先天性免疫特征更有利，但雄性小鼠的转移负担却增加了。我们的数据支持在与肿瘤以及可能的宿主激素环境相关的乳腺癌中存在性别依赖性免疫反应。随着针对肿瘤免疫微环境的新兴疗法的出现，表征免疫特征对于优化其在所有乳腺癌患者中的应用至关重要。
