The unique transcriptional profiles of tumor-associated macrophages and their progenitors, tumor-educated monocytes, have been used to develop diagnostic/prognostic gene signatures for breast and endometrial cancers and suggest potent therapeutic targets.

by Erica Langan

Exciting new research demonstrates the possibility of using the gene expression profiles of particular immune cell subsets to identify the aggressiveness and clinical outcomes of breast and endometrial cancers.

Mechanisms regulating the progression and severity of tumors are increasingly recognized to depend on interactions between cancerous cells and key populations of cells from the immune system, which often reside within the tumor microenvironment. Tumor-associated macrophages (TAMs) are one such immune cell subset, originating in the bone marrow as monocytes but migrating to tumors via the blood.

TAMs support cancer development by fostering the growth of new blood vessels to increase the availability of nutrients important for tumor growth, encouraging the metastasis of cancerous cells to other parts of the body, and impairing the ability of other cells of the immune system to kill tumor cells.

Although TAMs have been extensively studied in mouse models, the current body of knowledge regarding the function and transcriptional profiles of monocytes and TAMs in human tumors is limited and more in-depth analyses were warranted.

In a recent study published in Cancer Cell, Cassetta et al more closely examined the selection of proteins and other molecules manufactured by these cells with the goal of identifying potential biomarkers and therapeutic targets for breast and endometrial cancers.

Using RNA sequencing, the researchers were able to identify 865 genes expressed differently between monocytes implicated in the development of breast cancer (termed tumor-educated monocytes or TEMos) and those monocytes not involved in cancer progression.

Casseta et al used computer modeling to identify a 17-gene TEMo signature that, when tested on a population of 22 people (a combination of cancer patients and healthy individuals) yielded 82% accuracy, 100% sensitivity, and 69% specificity.

Remarkably, all cancer patients were correctly identified by the test but there were a few false negatives that indicate areas for improvement in this diagnostic measure. The researchers hope that this TEMo signature could be used as a reliable means to detect and prognose breast cancer from a liquid biopsy, which would offer a less invasive and cheaper method for assessing gene signatures than currently used tissue biopsies, serving as a complement or even a replacement for established diagnostic procedures.

Using gene expression profiling technologies, the researchers were able to analyze the TAMs that arise from TEMos in human breast and endometrial cancers and determine which genes were turned “on” and “off,” as well as the relative expression level of particular genes in each type of cell.

This information was consolidated into unique “transcriptional profiles” for each cell type. Through this procedure, significant differences were revealed between the transcriptional profiles of macrophages associated and not associated with tumors.

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There were also large differences between breast and endometrial TAMs, suggesting that TAM transcriptomes—the collections of RNA transcripts produced by a cell—are extremely varied and complex. Despite these challenges, Cassetta et al were able to determine a 37-gene TAM signature based on their own work and existing data from METABRIC, a Canada-UK project that contains a wealth of genetic information about breast cancer from around the world.

They then tested this signature by conducting whole-tumor RNA-sequencing on 47 breast cancer patients and evaluating the signature expression in these tumors. Since TAMs are a significant cell population in tumors, collecting RNA expression data from the entire tumor provided ample material to compare with the 37-gene signature.

Based on trends in their data, it appears that higher expression of the TAM signature is connected to more aggressive tumors and shorter disease-specific survival—in short, poorer clinical outcomes. With this in mind, this new TAM signature could be used in the future as a prognostic tool.

Lastly, Cassetta et al identified an important new genetic marker for human breast cancer, SIGLEC1, which participates with the soluble factor CCL8 in a positive regulatory loop to enhance tumor growth and development. The chemical pathways involved in this loop could be strong candidates for targeted inhibition, offering a new therapeutic tool.

These findings could be quickly translated to the clinic given that pharmacologic methods for inhibiting this pathway already exist and have been safely used in patients.

Cassetta L, Fragkogianni S, Sims AH, et al. (2019) Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets. Cancer Cell, 35(4), P588-602.E10. https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30104-7











