Stromal Cells Found to Act as Tumor Bodyguards in Bladder Cancer

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Gene expression of a biomarker linked to malignancies, found in stromal cell surrounding a tumor — not the tumor cells themselves — appears to prevent the action of checkpoint blockade.
Gene expression of a biomarker linked to malignancies, found in stromal cell surrounding a tumor — not the tumor cells themselves — appears to prevent the action of checkpoint blockade.

Researchers think they have found a biomarker that could be used to predict the ability of checkpoint inhibitors to work as intended — as well as their inability to produce a therapeutic result in bladder cancer.

The investigators, who were primarily from the Icahn School of Medicine at Mount Sinai in New York, New York, found that although epithelial-mesenchymal transition (EMT) gene expression is linked to an increase in T-cell infiltration — and in increase in EMT would generally be expected to cause a robust immune response — the increased expression of EMT in stromal cells surrounding the tumor microenvironment instead was associated with a worse response to checkpoint blockade, including shorter progression-free survival (PFS) and overall survival (OS).

When a tumor is “hot,” it is characterized by a large number of T cells infiltrating a tumor. But the investigators said that even patients with hot tumors don't always respond to checkpoint blockade.

The researchers tested their hypothesis about stromal cells with the help of Bristol-Myers Squibb and through use of genomic data drawn from The Cancer Genome Atlas.

Using a computational tool called ESTIMATE (estimation of stromal and immune cells in malignant tumor tissues using expression data), researchers concluded that the source of the EMT-related gene expression was likely from stromal cells near the tumor, rather than from epithelial cancer cells. In fact, patients with high levels of infiltrating T-cell abundance (ITA) and low levels of EMT in urothelial carcinoma had the best OS values, whereas patients with low ITA and high EMT had the worst OS.

To confirm that the source of EMT expression was from stromal cells, the researchers used mouse models of disease, though they did acknowledge that “11 of 18 of these genes demonstrated a higher proportion of reads from mouse than human.”1

The investigators also used data from the CheckMate 275 study to validate their findings about ITA and EMT signals via an analysis of targeted gene expression data from HTG Molecular's EdgeSeq platform. They said they used this tool over RNA sequencing because these assays “potentially have a clearer path to clinical application.”

They found that from the study cohort, low EMT levels in combination with high proportions of CD8 T cells was associated with a more robust response and better survival outcomes. Patients with high EMT and high immune-cell infiltration levels had worse outcomes.  “Together, these findings suggest that in CD8-infiltrated UC, EMT/stroma-related gene expression is associated with resistance to PD-1 blockade.”1

High EMT spatially restricts T cells from getting to tumors, the researchers reasoned, physically blocking immune cells from getting close enough to tumors to attack them.

Important study limitations include the fact that the assays used to measure T-cell infiltration differed across studies, and that “the impact of EMT-related gene expression on prognosis in cystectomy-treated patients with localized disease could reflect additional biological processes (eg, invasion, metastatic capacity, etc) beyond those related to immune modulation.”1 However, they concluded that the balance of EMT and ITA measurements on bladder cancer outcomes was still clinically striking, and may represent a better picture of potential antitumor response to checkpoint inhibitors than would measures of T cells alone.

Reference

  1. Wang L, Saci A, Szabo PM, at al. EMT-related and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer [published August 29, 2018]. Nat Commun.

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