Adipogenesis in triple-negative breast cancer is associated with unfavorable tumor immune microenvironment and with worse survival

Masanori Oshi,Lan Lee,Ryusei Matsuyama,Li Yan,Kazuaki Takabe,Fernando A Angarita,Itaru Endo,Yoshihisa Tokumaru

doi:10.1038/s41598-021-91897-7

Abstract

Cancer-associated adipocytes are known to cause inflammation; however, the role of adipogenesis, the formation of adipocytes, in breast cancer is unclear. We hypothesized that intra-tumoral adipogenesis reflects a different cancer biology than abundance of intra-tumoral adipocytes. The Molecular Signatures Database Hallmark adipogenesis gene set of gene set variant analysis was used to quantify adipogenesis. Total of 5,098 breast cancer patients in multiple cohorts (training; GSE96058 (n = 3273), validation; TCGA (n = 1069), treatment response; GSE25066 (n = 508) and GSE20194 (n = 248)) were analyzed. Adipogenesis did not correlate with abundance of adipocytes. Adipogenesis was significantly lower in triple negative breast cancer (TNBC). Elevated adipogenesis was significantly associated with worse survival in TNBC, but not in the other subtypes. High adipogenesis TNBC was significantly associated with low homologous recombination deficiency, but not with mutation load. High adipogenesis TNBC enriched metabolism-related gene sets, but neither of cell proliferation- nor inflammation-related gene sets, which were enriched to adipocytes. High adipogenesis TNBC was infiltrated with low CD8+ T cells and high M2 macrophages. Although adipogenesis was not associated with neoadjuvant chemotherapy response, high adipogenesis TNBC was significantly associated with low expression of PD-L1 and PD-L2 genes, and immune checkpoint molecules index. In conclusion, adipogenesis in TNBC was associated with cancer metabolism and unfavorable tumor immune microenvironment, which is different from abundance of adipocytes.

Highlights

Cancer-associated adipocytes are known to cause inflammation; the role of adipogenesis, the formation of adipocytes, in breast cancer is unclear
In order to examine whether the score reflect adipogenesis in patient breast cancer, we investigated the association of the score with several adipogenesis-related genes (Acetyl-CoA carboxylase/ACLY, ATP citrate lyase/ACACA, NADP-dependent malic enzyme/SLC25A10, and mitochondrial dicarboxylate carrier/ME1) and adipocyte-related genes in the GSE96058 and TCGA cohorts
High adipogenesis triple negative breast cancer (TNBC) was significantly associated with low expression of PD-L1 and PD-L2, which are major immune checkpoint molecules in both GSE96058 and TCGA cohorts (Fig. 6B)

Summary

Introduction

Cancer-associated adipocytes are known to cause inflammation; the role of adipogenesis, the formation of adipocytes, in breast cancer is unclear. Adipogenesis in TNBC was associated with cancer metabolism and unfavorable tumor immune microenvironment, which is different from abundance of adipocytes Both breast cancer screening and advancement in therapeutics have significantly improved the prognosis of breast cancer patients. We previously reported that intra-tumoral adipocytes are associated with inflammation and metastasis but with less cell proliferation and better patient survival using multiple large breast cancer cohorts with t ranscriptomes[12]. These data suggest that abundance of intra-tumoral adipocytes inversely reflects the cancer cell density of the bulk tumor less aggressive cancer. This method has been widely used to score pathway activity from global gene expression data thereby showing the clinical relevance of G2M checkpoint[17], E2F targets[18], MYC targets[19], KRAS signaling up[20], estrogen response[21] and angiogenesis pathway[22] in breast cancer

Methods

Results

Conclusion