Tumor and Host Determinants of the Breast Tumor Immune Microenvironment in Kenyan Breast Cancer Women

Background: The tumor immune microenvironment (TIME) reflects both tumor-intrinsic biology and host-modifiable factors. Characterizing how tumor features, body mass index (BMI), and reproductive history relate to immune activity may help explain heterogeneity in breast cancer and inform precision prevention and survivorship strategies. Methods: We analyzed 461 invasive breast tumors from Kenyan patients using a custom NanoString nCounter® immune-focused gene panel. Intrinsic subtypes were assigned with PAM50, and immune cell composition (relative proportions for 22 immune cells) was estimated by CIBERSORTx. Composite immune activity scores were derived to represent functional modules: z_hot (CD8+, M1 macrophages, NK activated, T follicular helper) and z_suppression (Treg + M2 macrophages) from CIBERSORTx; z_cytotoxic (GZMB, PRF1) , z_exhaustion (PDCD1, LAG3, CTLA4) , and z_checkpoint ( PDCD1, PDCD1LG2, CTLA4, LAG3 ) from GSVA signatures. Associations between immune scores and tumor features (PAM50 subtypes, risk of recurrence (ROR), RNA-based TP53 status, tumor grade) or host factors (BMI, menopausal status, parity, breastfeeding) were evaluated in age-adjusted linear regression models. Independent effects of host factors were further examined in multivariable regression models adjusted for tumor characteristics and lifestyle covariates. Multiple testing was accommodated using a false discovery rate adjusted p -values. Results: Participants had a mean age of 50.3 years; 43.8% of tumors were luminal A and 21.5% basal-like. Most women were overweight/obese (BMI ≥ 25, 73.1%) and 65.7% had ≥ 3 children. High-grade, basal-like, high-ROR, and TP53 mutant-like tumors showed strong evidence of elevated z_hot , z_cytotoxic , z_checkpoint , and z_exhaustion scores (BH-adjusted p < 0.001), along with modestly lower z_suppression in basal-like and TP53 mutant-like tumors ( p < 0.05), indicating an active TIME characteristic of aggressive tumors. In contrast, established BC risk factors showed weaker influence on TIME. Overweight/obese patients were more likely to have cold TIME (lower CD8 ( p = 0.09), T follicular helper ( p < 0.05), and z_hot score ( p < 0.05)), while patients with longer duration of breastfeeding had more active TIME (higher T follicular helper and z_cytotoxicity; lower M2 macrophages and z_suppression (all p < 0.05)). Conclusions: Tumor-intrinsic subtype classification remains the dominant determinant of immune heterogeneity, while established BC risk factors (BMI and reproductive risk factors) may modulate immune responsiveness. Integrating tumor, reproductive, and lifestyle data can help clarify immune variation across diverse populations.