可改变的生活方式因素与乳腺肿瘤及癌旁正常组织中的免疫基因表达

Background: The tumor immune microenvironment may provide key information on breast cancer prognosis. Several modifiable risk factors influence the immune response, including weight, physical activity, and diet; however, whether these factors alter the breast tumor immune microenvironment remains unknown. Methods: Participants enrolled in the Nurses' Health Studies diagnosed with invasive breast cancer and available tumor and/or normal adjacent tissue were included (N=945). Immune cell abundance was deconvoluted using CIBERSORTx. Gene expression signatures were derived for components of the immune profile such as immune checkpoint markers, co-regulatory signal and antigen presentation, and cytokine signaling. Participant weight, BMI, alcohol use, and smoking status were collected via bi-annual questionnaires. Overall diet was summarized by the alternative healthy eating index (AHEI) and the empirical dietary inflammatory pattern (EDIP), derived from food frequency questionnaires completed every 4 years. Linear regression was used to test the association between pre-diagnostic exposures (from questionnaires closest to diagnosis) and immune cell abundance and gene expression. Tumor and normal-adjacent tissue were analyzed separately. Models were adjusted for year and age of diagnosis, menopausal status, and estrogen-receptor (ER) status. Multiple testing of immune components was controlled via the false discovery rate. Models were also stratified by ER and menopausal status. Results: Among 875 women with available tumor tissue, mean age at diagnosis was 59 years (SD=11.4). The majority (73%) were post-menopausal, had ER-positive tumors (77%), and were diagnosed at stage 1-2 (91%). In ER-positive tumor tissue of postmenopausal women, weight gain since age 18 was positively associated with interferon signaling, MHCII, and PD1 expression (all p adj <0.05). Higher physical activity was associated with enriched CD8:CD68 ratio in this group. In ER-negative tumor tissue of pre- and postmenopausal women, consuming more drinks per week was associated with higher PDL1 and lower CSR expression. In normal-adjacent tissue, current smoking was associated with enriched cytokine signaling in premenopausal women and total pack-years was associated with higher B cell plasma in postmenopausal women. Higher EDIP was associated with heightened MHCII and IL12 expression in ER-negative tumor tissue while higher AHEI was associated with lower lymphocyte infiltration expression in normal adjacent tissue, regardless of menopausal status. Conclusions: Weight gain, smoking, alcohol use, and diet (AHEI and EDIP) are associated with differences in the breast cancer immune microenvironment, with distinct associations by ER and menopausal status. Changes in lifestyle behaviors may influence the tumor immune response and impact patient prognosis, though further studies are needed.