RNA-Sequencing Assists Immunotherapy Decision Strategies for Patients with Metastatic Bladder Cancer

Patients with metastatic urothelial bladder cancer have had few treatment options beyond platinum-based chemotherapies, until the recent introduction of immunotherapy via PD-1 and PD-L1 checkpoint inhibitors. However, checkpoint-inhibitor immunotherapy has been shown to provide significant benefits to a relatively small subset of patients, and in some cases it can cause dangerous side effects such as organ-related inflammation. Hence the need for precision medicine solutions to find biomarkers identifying the patients who might gain the full benefit from these PD-1/PD-L1 inhibitors alone or in combination therapies. A recent study published in Clinical Cancer Research has revealed an RNA-sequencing-based methodology which looks able to do just that.

Credit : National Cancer Institute
Relying on advances in RNA sequencing, scientists at Mount Sinai’s Icahn School ofMedicine studied bulk RNA sequencing data from the IMvigor 210 and CheckMate 275 clinical trials along with innovative, single-cell RNA sequencing data from additional patients and The Cancer Genome Atlas. This provided them with a much more precise view and understanding of bladder tumor micro environments, enabling them to answer questions about, for example, the number of T cells on a given tumor, how immune cells are infiltrating a tumor, how the tumor environment behaves, and more.

This more refined understanding helped the researchers uncover two new gene expression signatures, or biomarkers, connected to PD-1/PD-L1 checkpoint inhibitor immunotherapy. The first biomarker identifies how it benefits some patients (those who experience adaptive immunity), and the second identifies those who do not respond or develop resistance to it (those who experience pro-tumorigenic inflammation, also known as tumor-promoting inflammation). Then, by studying the ratio, or balance, between these two signatures in a given tumor environment the researchers found that it can reveal those patients for whom these therapies would likely be most successful. They named the ratio the “2IR Score.”

According to Mount Sinai, “If the tumor microenvironment is weighted more toward adaptive immunity, there’s a better chance of positive outcomes from immunotherapy,” explains Dr. Galsky, who is Associate Director of Translational Research and Co-Director of the Bladder Cancer Center of Excellence at The Tisch Cancer Institute. “On the other hand, if the tumor microenvironment is leaning toward pro-tumorigenic inflammation, then PD-1/PD-L1 checkpoint inhibitors alone are unlikely to be successful, and new combination approaches may be needed.”

Furthermore, RNA-sequencing led the researchers to drill down and identify a subset of white blood cells known as myeloid phagocytic cells, which have been linked to resistance to check point inhibitor immunotherapy due their tumor-promoting inflammation properties.


As reported by Precision Oncology News, “when the researchers applied their 2IR score to single myeloid phagocytic cells — a Msc2IR score — they found that myeloid phagocytic cells with low scores upregulated proinflammatory cytokines and chemokines and downregulated antigen receptor genes and were enriched among patients with treatment-resistant urothelial cancer, suggesting this cell type could account for treatment resistance.”

Sharing that he and his colleagues are incorporating these strategies into upcoming clinical trials, Dr. Galsky noted:

"Our research shows that a specific cellular state of myeloid cells underlying pro-tumorigenic inflammation accounts for resistance to immune checkpoint blockade in a very large percentage of patients with urothelial bladder cancer. This is an important finding which we believe can lead to a better focus and direction for developing effective combination therapies — and not just for bladder cancer, but other types of tumors, as well.”

In summary, this study illustrates the benefits of extending the search for actionable molecular information beyondDNA. RNA-sequencing can uncover new biomarkers and help match patients, particularly those with metastatic disease, to the most potentially beneficial treatments.

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