Pierro Elysa W, Cottam Matthew A, An Hanbing, Lehmann Brian D, Pietenpol Jennifer A, Wellen Kathryn E, Makowski Liza, Rathmell Jeffrey C, Fingleton Barbara, Hasty Alyssa H
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee.
Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Cancer Res. 2025 Apr 3;85(7):1219-1235. doi: 10.1158/0008-5472.CAN-24-3511.
Obesity is an established risk factor for breast cancer development and poor prognosis. The adipose environment surrounding breast tumors, which is inflamed in obesity, has been implicated in tumor progression, and triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane receptor expressed on macrophages in adipose tissue and tumors, is an emerging therapeutic target for cancer. A better understanding of the mechanisms for the obesity-breast cancer association and the potential benefits of weight loss could help inform treatment strategies. In this study, we utilized lean, obese, and weight-loss mouse models to examine the impact of TREM2 deficiency on postmenopausal breast cancer depending on weight history conditions. Trem2 deficiency constrained tumor growth in lean, but not in obese or weight-loss, mice. Single-cell RNA sequencing, in conjunction with variable-diversity-joining sequencing, of tumor and tumor-adjacent mammary adipose tissue immune cells revealed differences in the immune landscapes across the different models. Tumors of lean TREM2-deficient mice exhibited a shift in clonal CD8+ T cells from an exhausted to an effector memory state, accompanied by increased clonality of CD4+ Th1 cells, that was not observed in any other diet-genotype group. Notably, identical T-cell clonotypes were identified in the tumor and tumor-adjacent mammary adipose tissue of the same mouse. Finally, anti-PD-1 therapy restricted tumor growth in lean and weight-loss, but not in obese, mice. These findings indicate that weight history could affect the efficacy of TREM2 inhibition in postmenopausal breast cancer. The reported immunologic interactions between tumors and the surrounding adipose tissue highlight significant differences under obese and weight-loss conditions. Significance: Weight history impacts the immunological landscape of postmenopausal breast cancer and the efficacy of TREM2 modulation and anti-PD-1 therapy, which has implications for personalized medicine.
肥胖是乳腺癌发生和预后不良的既定风险因素。乳腺肿瘤周围的脂肪环境在肥胖状态下会发生炎症，这与肿瘤进展有关，而髓样细胞2上表达的触发受体（TREM2）是一种在脂肪组织和肿瘤中的巨噬细胞上表达的跨膜受体，是癌症新兴的治疗靶点。更好地理解肥胖与乳腺癌关联的机制以及减肥的潜在益处有助于为治疗策略提供依据。在本研究中，我们利用瘦型、肥胖型和减肥小鼠模型，根据体重历史状况来研究TREM2缺陷对绝经后乳腺癌的影响。Trem2缺陷抑制了瘦型小鼠的肿瘤生长，但在肥胖或减肥小鼠中则没有。对肿瘤及肿瘤邻近乳腺脂肪组织免疫细胞进行单细胞RNA测序，并结合可变多样性连接测序，揭示了不同模型之间免疫格局的差异。瘦型TREM2缺陷小鼠的肿瘤中，克隆性CD8+T细胞从耗竭状态转变为效应记忆状态，同时CD4+Th1细胞的克隆性增加，而在其他饮食-基因型组中未观察到这种情况。值得注意的是，在同一只小鼠的肿瘤及肿瘤邻近乳腺脂肪组织中鉴定出了相同的T细胞克隆型。最后，抗PD-1疗法在瘦型和减肥小鼠中限制了肿瘤生长，但在肥胖小鼠中则没有。这些发现表明体重历史可能会影响TREM2抑制在绝经后乳腺癌中的疗效。报道的肿瘤与周围脂肪组织之间的免疫相互作用突出了肥胖和减肥条件下的显著差异。意义：体重历史影响绝经后乳腺癌的免疫格局以及TREM2调节和抗PD-1疗法的疗效，这对个性化医疗具有重要意义。
