Abstract PS16-09: High infiltration of adipocytes is associated with inflammation, metastasis as well as favorable tumor immune microenvironment whereas low infiltration is associated with highly proliferative tumor in ER positive breast cancer patients
Authors: Tokumaru Yoshihisa , Oshi Masanori , Katsuta Eriko , Matsuhashi Nobuhisa , Futamura Manabu , Yoshida Kazuhiro , Takabe Kazuaki 
Published: February 2021

Abstract
Background: Cancer associated adipocytes are known to cause inflammation and leads to the cancer progression, and metastasis. In the current study, we defined intra-tumoral adipocytes transcriptionally utilizing a computational algorithm, xCell, which allowed us to quantify infiltrating adipocytes. We hypothesized that high amount of intra-tumoral adipocytes is associated with aggressive cancer characteristics and poor survival outcome.
Material and Methods: The clinicopathological data and survival information of 1090 breast cancer patients were obtained from The Cancer Genome Atlas (TCGA), GSE25066 and study by Yau et al. Survival analysis, gene set enrichment analysis (GSEA) were conducted comparing the intra-tumoral adipocyte high and low groups. The association between the amount of intra-tumoral adipocytes and Nottingham pathological grade or AJCC stage were evaluated. CYT score and xCell were utilized to evaluate intratumoral immune cell composition within breast cancer.
Results: Our transcriptomically defined intra-tumoral adipocyte appropriately reflected mature adipocytes in a bulk tumor. Surprisingly, intra-tumoral adipocytes high tumors did not demonstrate worse survival, neither OS or DFS, in the whole cohort or any of the subtypes. Less aggressive Stage 1 even trended toward increased intra-tumoral adipocytes although statistically insignificant. Further, less proliferative grade 1 was associated with increased intra-tumoral adipocytes compared with other grades in whole and ER positive/HER2 negative (ER+/HER2-) subtype of TCGA cohort (p &lt; 0.001). This result was consistent in GSE25066 cohort (p &lt; 0.001). An amount of intra-tumoral adipocytes was weakly inversely correlated with MKI67 expression in three cohorts; TCGA, GSE25066 and the study by Yau et al (r = -0.235, r = -2.09 and r = -0.355, respectively). In agreement with the previous in vitro studies, adipocyte high tumors enriched the gene sets associated with inflammation, such as TNF-α and Inflammatory response. Further, intra-tumoral adipocyte high tumors enriched the gene sets related to metastasis, such as EMT, TGF-β signaling, and Notch signaling. On the other hand, adipocyte high tumors enriched the gene sets related to immune response such as IL2 signaling and IFN-γ especially in ER+/HER2- subtype. The analysis of tumor immune microenvironment revealed that intra-tumoral adipocyte high tumors were associated with favorable tumor immune microenvironment in ER+/HER2- subtype, but not in triple negative (TN). Consistent with the association with pathological grade and MKi67, intra-tumoral adipocyte low tumors enriched the cell cycle and cell proliferation gene sets, such as G2M checkpoint, in both TCGA and GSE25066 cohorts. These results force us to speculate that intra-tumoral adipocytes does cause inflammation and evoke metastatic pathways as previously reported in in vitro studies, but also associate with immune response, whereas adipocyte low tumors are highly proliferative cancers, thus, there are no difference in clinical outcome between them.
Conclusion: High infiltration of adipocyte was associated with inflammation, metastatic pathways and favorable tumor immune microenvironment, whereas low infiltration of adipocytes was associated with highly proliferative tumor in ER-positive breast cancer. These cancer biologies may explain the reason why adipocyte infiltration high tumors did not demonstrate worse survival.
Citation Format: Yoshihisa Tokumaru, Masanori Oshi, Eriko Katsuta, Nobuhisa Matsuhashi, Manabu Futamura, Kazuhiro Yoshida, Kazuaki Takabe. High infiltration of adipocytes is associated with inflammation, metastasis as well as favorable tumor immune microenvironment whereas low infiltration is associated with highly proliferative tumor in ER positive breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-09.