Abstract PD4-06: PD4-06 Obesity-associated changes in transcriptomic profile and immune landscape of primary breast cancer revealed by bulk and single-cell gene expression data

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Abstract Background: Breast cancer (BC) is one of the cancer types recognized as an obesity-associated disease. Current understandings of molecular mechanisms underlying the BC-obesity connection however largely came from experimental models while systematic investigation of the impact of obesity on BC biology in large patient series is still lacking. The purpose of this study is to discover changes in the transcriptomic profile of primary BC according to patients’ body mass index (BMI). Data and Methods: Bulk and single-cell gene expression data from treatment-naïve primary breast tumors from non-underweight patients were retrieved from the MINDACT trial (NCT00433589; N = 1481) and the pre-treatment cohort of the BioKey trial (NCT03197389, N = 36), respectively. Three categories were considered for BMI: lean, overweight and obese. The main analyses focused on the invasive carcinoma of no special type (NST) estrogen receptor-positive/HER2-negative (ER+/HER2-, N_bulk = 735, N_single-cell(sc) = 10) and NST ER-/HER2- (N_bulk = 118, N_sc = 15) subgroups. The bulk expression data was subjected to differential gene expression analyses according to BMI which was adjusted for menopausal status and tumor grade, then followed by gene set enrichment analyses. Clustering and cluster annotation were performed on the single-cell profiling data before differentially expressed genes according to BMI were identified for each of the present cell types. Results: Obesity-associated differences in the transcriptomic profile of breast tumors, which were subtle but potentially indicative of a biological relationship, were revealed by the bulk data. In both investigated subgroups, tumors from obese patients were shown to be enriched in cell cycle hallmarks. In ER-/HER2- tumors, adiposity further increased MYC signaling. We also observed different obesity-associated changes according to the ER status. Among ER+/HER2- tumors, those from obese patients were enriched in hallmarks related to inflammatory response compared to those from lean patients. In contrast, these hallmarks appeared to be enriched in the ER-/HER2- tumors from lean patients. Our investigation of the single-cell data further revealed shifts in the cell composition of tumor tissue and cell type-specific transcriptomic differences according to BMI which were more pronounced than those detected from the bulk data. ER+/HER2- tumors from obese patients have a higher frequency of immunosuppressive and pro-tumoral cell subpopulations such as dendritic cells (DC) enriched in immunoregulatory molecules (p = .03), LYVE1+ macrophages (p = .02) and myofibroblasts (p = .03) than those from lean patients. Overexpression of Cyclin D1 and CD24 was found in cancer cells in ER+/HER2- tumors from obese patients. A reduction in anti-tumor immune responses was evident with downregulation of multiple interferons in CD8+ and CD4+ T cells as well as B cells. We observed in the ER-/HER2- subgroup increased infiltration of plasmacytoid DC (p = .01), CCL2+ macrophages (p = .01) in tumors from obese versus lean patients, while fibroblasts showed an opposite tendency. Additionally, significant obesity-associated downregulation of major histocompatibility complex (MHC) molecules class I in cancer cells and MHC class II molecules in B cells could be suggestive of deficient antigen presentation and activation of cytotoxic and helper T cells. Conclusion: We highlighted the impact of obesity on the remodeling of tumor and tumor microenvironment which might generally lead to a suppression of anti-tumor immune responses, albeit potentially via diverse axes according to the ER status. Although investigation on a larger cohort is warranted, our current results suggest that obesity-associated transcriptomic changes in BC could be highly cell type-specific, hence we recommend single-cell approaches in addition to spatial multi-omics analysis to further elucidate the interplay between obesity and BC. Citation Format: Ha-Linh Nguyen, Tatjana Geukens, Marion Maetens, Karen Van Baelen, Maxim De Schepper, Coralie Poncet, Mauro Delorenzi, Marjanka K. Schmid, Emiel Rutgers, Laura Van ’t Veer, Martine Piccart, Fatima Cardoso, Giuseppe Viale, Ayse Bassez, Hanne Vos, Patrick Neven, Ines Nevelsteen, Kevin Punie, Hans Wildiers, Giuseppe Floris, Diether Lambrechts, Ann Smeets, Elia Biganzoli, François Richard, Christine Desmedt. PD4-06 Obesity-associated changes in transcriptomic profile and immune landscape of primary breast cancer revealed by bulk and single-cell gene expression data [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD4-06.