Background: Breast and endometrial cancers are two of the most frequently diagnosed reproductive cancers in women in the western world. Previously, research has focused on cancer cells, however increasing evidence shows that the tumour microenvironment plays an important role in cancer progression. Macrophages are almost entirely derived from circulating monocytes and are recruited into tumour sites. In murine studies, tumour-associated macrophages (TAMs) have been implicated in promoting angiogenesis, immune suppression and resistance to treatment. Their density has been associated with poor prognosis in breast cancer and decreased survival in endometrial cancer. However, little is known about the function of TAMs in humans. The aim of this study is to examine the transcriptional profiles of human TAMs in order to investigate their biological relevance and potential for therapeutic intervention.

Methods: RNA-sequencing was performed on purified normal macrophages and TAMs from breast tissue (4 breast cancer and 4 healthy breast) and endometrium tissue (5 endometrial cancer and 9 healthy endometrium). Statistical analysis using Limma was used to identify significantly differentially expressed genes (FDR< 0.05) with a minimum log2 fold change of 1.5. Gene set enrichment (GSEA) analysis and gene ontologies (GO) were employed for functional analysis and identification of important biological pathways.

Results: Transcriptome profiling revealed a significantly altered gene expression profile of TAMs when compared to normal macrophages. Furthermore, comparison of TAMs between breast and endometrial cancer also revealed differences suggesting that different tumour microenvironments induce different gene expression profiles in TAMs. Interestingly, comparison of normal macrophages between breast and endometrial tissue also revealed differences in gene expression suggesting tissue specificity for macrophages. Functional analysis of significant genes revealed similar biological pathways to those of murine studies suggesting that TAMs in humans may have similar functions. We were able to extract TAM-specific genes by comparing with publicly available datasets that could serve as markers for their identification. Finally, we identified a list of transmembrane receptors that could act as potential targets for targeted killing of TAMs.

Conclusion: This is the first study to carry out genome-wide profiling of TAMs in human breast and endometrial cancer. Expression profiles differed between TAMs and healthy patients, as well as between breast and endometrial cancer suggesting cancer specificity for TAMs and revealing not only potential TAM-specific markers, but also identifying possible cancer- and TAM-specific therapeutic targets.

Citation Format: Matina Fragkogianni, Luca Cassetta, Agnieszka Swierczak, Lisa Wiechmann, Harriet O. Smith, Andrew H. Sims, Hui Zhang, Lisa M. Coussens, J. W. Pollard. Transcriptional profiling of human TAMs highlights differences in breast and endometrial tumour microenvironments. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2698.