Comparison of Lean, Obese, and Weight-Loss Models Reveals TREM2 Deficiency Attenuates Breast Cancer Growth Uniquely in Lean Mice and Alters Clonal T-cell Populations

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.