Abstract B016: Genomic features of the tumor microenvironment and antigen presentation machinery vary by clinical and molecular subtypes of breast cancer
Authors: Constandina E O'Connell, Yoon Jin Cha, Alexander V Lobanov, Cheng Fan, Brooke M Felsheim, Aranzazu Fernandez-Martinez, Charles M Perou
Journal: Cancer Research (2025)

Abstract Breast cancer is a heterogeneous malignancy where precision medicine approaches have informed treatment decisions; currently, these decisions are largely driven by IHC subtyping based on the expression of targetable receptor proteins (ER, PR, and HER2). Between clinical subtypes, immune cell infiltration and its prognostic impact vary considerably. Tumor-infiltrating lymphocytes (TILs) are most common in triple-negative breast cancers and are associated with improved patient prognosis. In contrast, TILs are less abundant on average in ER+/HER2- tumors, and their presence is much less prognostic. These contrasting data point to distinct roles for the immune system in different breast cancer subtypes, which will be crucial to understand for optimal application of immunotherapy. Using the multi-platform TCGA-BRCA dataset (n=1035 tumors), we evaluated stromal TILs from H&amp;E images and then compared the microenvironments of high-TIL tumors by clinical and molecular subtype using 250+ pre-determined immune signatures calculated from bulk RNA sequencing of the same tumors. We identified unique immune signatures highly expressed in each subtype: granulocytes and interferon signaling were more abundant in luminal/ER+ tumors, while HER2-enriched and basal-like tumors had elevated signature scores related to B and T cells, respectively. Major histocompatibility complex Class I (MHC-I) antigen presentation is another key immune pathway that can vary by tumor subtype. Further, loss or downregulation of MHC-I genes, including HLA-A, is a prevalent mechanism of immune evasion in breast cancer. Using bulk and single-cell RNA sequencing (scRNAseq), we found that ER+/Luminal tumor cells express low levels of HLA-A, while TNBCs/basal-like tumor cells express high levels. HLA-A also has subtype-specific associations with survival, where high HLA-A expression predicts better outcomes in TNBC but worse outcomes in ER+ patients. We therefore hypothesized that MHC-I may have distinct roles in different subtypes of breast cancer. Preliminary data from a cohort of 108 human breast tumor scRNAseq samples indicate that HLA-A expression in ER+/Luminal tumors may be associated with more stromal infiltration, while HLA-A in TNBCs is associated with more immune cell infiltration. Additionally, we hypothesized that ER/PR signaling may play a role in the low levels of HLA-A expression observed in ER+/Luminal tumors. Using a scRNAseq dataset of short-term cultures of ER+ human breast tumors treated with tamoxifen, we found an association between PR levels and induction of HLA-A expression following tamoxifen treatment, such that PR-high tumors were more likely to upregulate HLA-A following tamoxifen. Overall, these data support that the immune microenvironments of breast tumor molecular subtypes are distinct and likely influenced by tumor cell-intrinsic features. These attributes will be important to guide the development and implementation of precision immunotherapy approaches and may have utility in the future as biomarkers to guide treatment strategies. Citation Format: Constandina E O'Connell, Yoon Jin Cha, Alexander V Lobanov, Cheng Fan, Brooke M Felsheim, Aranzazu Fernandez-Martinez, Charles M Perou. Genomic features of the tumor microenvironment and antigen presentation machinery vary by clinical and molecular subtypes of breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B016.