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.