RNA-Sequencing Predicts Immunotherapy Success in Bladder Cancer

Urothelial carcinoma, also known as transitional cell carcinoma (TCC), is by far the most common type of bladder cancer. Urothelial cells also line other parts of the urinary tract, such as the part of the kidney that connects to the ureter (called the renal pelvis), the ureters, and the urethra.

The standard treatment for metastatic urothelial cancer of the bladder has been platinum-based chemotherapy, though the landscape has changed dramatically in recent years with the advent of PD-1 and PD-L1 immune checkpoint inhibitors, but only 20% to 25% of patients with bladder cancer respond to treatment.

A multidisciplinary team of medical scientists led by Icahn School of Medicine at Mount Sinai, New York, NY, USA) uncovered gene signatures representing adaptive immunity and pro-tumorigenic inflammation that were responsible for sensitivity or resistance to immune checkpoint inhibitors, drugs that help the body's immune system recognize and attack cancerous cells. The team used both bulk and single-cell RNA sequencing of human bladder tumors to study resistance to immunotherapy. Bulk sequencing examines the mix of genes expressed by every individual cell within a tumor, while single-cell sequencing zeroes in on gene expression by each individual cell, which yields unprecedented knowledge of the complexity and heterogeneity of cells that comprise tumors.

The scientists reported that the adaptive immune response:protumorigenic inflammation signature expression ratio, coined the 2IR score, best correlated with clinical outcomes, and was externally validated. Mapping these bulk gene signatures onto scRNA-seq data uncovered their underlying cellular diversity, with prominent expression of the protumorigenic inflammation signature by myeloid phagocytic cells.

However, heterogeneity in expression of adaptive immune and protumorigenic inflammation genes was observed among single myeloid phagocytic cells, quantified as the myeloid single cell immune:protumorigenic inflammation ratio (Msc2IR) score. Single myeloid phagocytic cells with low Msc2IR scores demonstrated upregulation of proinflammatory cytokines/chemokines and downregulation of antigen presentation genes, were unrelated to M1 versus M2 polarization, and were enriched in pretreatment blood samples from patients with PD-L1 blockade–resistant metastatic urothelial cancer.

Matthew D. Galsky, MD, a Professor of Medicine and senior author of the study, said, “If the tumor microenvironment is weighted more toward adaptive immunity, there's a better chance of positive outcomes from immunotherapy. 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.”

The authors concluded that the balance of adaptive immunity and protumorigenic inflammation in individual tumor microenvironments is associated with PD-1/PD-L1 resistance in urothelial cancer with the latter linked to a proinflammatory cellular state of myeloid phagocytic cells detectable in tumor and blood. The study was published on April 9, 2021 in the journal Clinical Cancer Research.

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Icahn School of Medicine at Mount Sinai