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Gene Expression Score IDs PD-1/PD-L1 Immune Checkpoint Inhibitor Resistance in Bladder Cancers

NEW YORK ­— The ratio of two gene expression scores may reveal whether urothelial cancer is susceptible to PD-1/PD-L1 immune checkpoint inhibitors, a new study has found.

Until recently, urothelial cancer was largely treated with platinum-based chemotherapy, but PD-1/PD-L1 immune checkpoint inhibitors have recently emerged as another treatment option. While such treatment can lead to lasting responses among urothelial cancer patient, that only occurs in only about 15 percent to 25 percent of patients. Researchers have been searching for biomarkers or other molecular hints that might mark additional urothelial cancer patients who might benefit from such treatment.

Using RNA-sequencing data from two clinical trials in combination with single-cell sequencing data from additional patients, a team led by researchers at the Icahn School of Medicine at Mount Sinai uncovered gene expression signatures associated with either adaptive immunity and improved outcomes with PD-1/PD-L1 immune checkpoint inhibitor treatment or with pro-tumorigenic inflammation and treatment resistance.

As they reported on Friday in Clinical Cancer Research, the balance of the two signatures, which the researchers expressed as a ratio they dubbed the 2IR Score, could then tip treatment response in one or the other direction. They further traced the resistance signature score to myeloid cells, indicating a role for them in treatment response.

In addition to identifying patients who may be sensitive or resistant to PD-1/PD-L1 blockade, the approach could also determine which patients might benefit from combination therapy, senior author Matthew Galsky, a professor of hematology and medical oncology at Mount Sinai, said in an email.

"We believe that the most important application of this work may not be simply in determining which patients are sensitive versus resistant, but rather identifying for which patients intrinsic resistance to PD-1/PD-L1 blockade might be overcome with particular combination strategies targeting a specific population of myeloid cells that might be driving resistance," Galsky said.

To uncover those signatures, the researchers analyzed bulk RNA-sequencing data from samples collected prior to treatment from the IMvigor 210 study, which examined Roche's Tecentriq (atezolizumab) in patients with metastatic urothelial carcinoma.

With these samples and additional data from The Cancer Genome Atlas, the researchers homed in on a set of 483 genes that were consistently co-expressed and associated with longer overall survival. These genes were also enriched for adapted immune response genes, leading the researchers to dub this the adaptative response signature.

They similarly zeroed in on a set of 437 genes that were enriched for inflammation and innate immune genes that they then labeled the pro-tumorigenic inflammation signature.

By combining these two signatures, they formed the 2IR score that measures a tumor's balance between adapted immune response and pro-tumorigenic inflammation. They validated their score using data from the CheckMate 275 study, which examined nivolumab in patients with metastatic urothelial cancer.

Meanwhile, the researchers analyzed single-cell sequencing data from primary urothelial tumors to determine which cells in a tumor expressed the adaptative response signature and the pro-tumorigenic inflammation signature. From this, they found some heterogeneity, with some cell types mostly expressing one signature, but sometimes the other.

In particular, though, they focused on myeloid phagocytic cells, which have been linked to the suppression of anti-tumor immunity, and found that those cells tended to express the pro-tumorigenic inflammation signature.

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.

According to Galsky, he and his colleagues are about to start new combination studies examining ways to overcome resistance in tumors with low 2IR scores as well as a Phase 3 study to further validate their findings by examining PD-L1 blockade in combination with a therapy that is thought to target immune-suppressive myeloid cells.

He noted that while this is an analysis they are considering commercializing, their "most important goal is to try and extend the marked benefits with immune checkpoint blockade that we see in a small subset of patients with metastatic bladder (urothelial) cancer to a much broader patient population."