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Study Finds Potential Biomarkers for Checkpoint Inhibitor Response in Melanoma

NEW YORK – In the oncology field, there has been much focus on understanding the role of tumor mutational burden as a predictive biomarker for immunotherapy amid conflicting findings.

Now, in a study published last week in Nature Communications, a group of researchers has found that two major components of the immunoproteasome are associated with survival in melanoma patients and response to checkpoint inhibitors.

The authors, led by Shelly Kalaora and Yardena Samuels from the Weizmann Institute of Science in Israel, further suggested that these markers may be better predictive than tumor mutational burden and may be worth exploring in larger studies.

"We find that PSMB8 and PSMB9 expression levels are much stronger predictors of melanoma patients' immune response to checkpoint inhibitors than the tumors' mutational burden," Samuels and colleagues wrote in the paper. "These results suggest that PSMB8 and PSMB9 expression levels can serve as important biomarkers for stratifying melanoma patients for immune-checkpoint treatment."

Previously, it has been demonstrated that the immunoproteasome subunits PSMB8 and PSMB9 are overexpressed in melanoma cell lines. The researchers wanted to understand this connection by analyzing the genomic and transcriptomic alteration data in melanoma patients from The Cancer Genome Atlas (TCGA).

They found a high frequency of amplification and overexpression of the PSMB8 and PSMB9 genes in melanoma patients, and their overexpression led to enhanced activity of tumor infiltrating lymphocytes against melanoma cells. This is due to an altered presentation of antigens that occur after the immunoproteasome overexpression, which improves the immune response, leading to higher survival rates and an improved response to both anti-CTLA4 and anti-PD1 checkpoint inhibitors.

The researchers used human leukocyte antigen (HLA) peptidomics to analyze the changes in the HLA peptide repertoire of melanoma cells due to PSMB8 and PSMB9 overexpression. They found that with PSMB8 and PSMB9 overexpression, the collection of antigens presented, including neoantigens and tumor-associated antigens, is also altered. Specifically, there were more presented peptides in cells overexpressing the immunoproteasomes compared to the control.

The tumor-associated antigens and neoantigens that were differentially presented by cells that overexpress the immunoproteasome subunits elicited a higher immune response compared to the antigens presented by the control cells. The researchers wrote that the improved immune response is a result of the production of more immunogenic antigens by the cells with higher immunoproteasome expression.

PSMB8 and PSMB9 overexpression was also found to be associated with CD4-positive and CD8-positive T-cell infiltration, regulatory T-cells, NK cells, and M1-macrophages. This suggested to the researchers that longer overall survival is supported by the immunoproteasome subunits' effects on T-cell cytotoxicity.

The team then used CIBERSORT — a method developed by Stanford University researchers to characterize the cell composition of complex tissues using gene expression profiling  — and found that several of these different immune markers, such as an interferon gamma signature and T-cell infiltration, are associated with patient survival. However, statistical analysis further showed overexpression of the immunoproteasome subunits predicted for patient survival independently of these other markers.  

Then, the researchers analyzed expression data from recent studies where melanoma patients were treated with immune-checkpoint therapies to determine whether patient drug response is correlated with PSMB8 and PSMB9 levels.

The researchers looked at 26 tumor samples of patients treated with the anti-CTLA4 drug ipilimumab (Bristol-Myers Squibb's Yervoy) for gene expression, mutation, and response annotation. In this population, there were nine responders and 17 non-responders. Six out of nine tumors with high immunoproteasome subunit expression and high mutational load had a durable clinical benefit to anti-CTLA4 therapy. None of the eight patients whose tumors exhibited low immunoproteasome subunit expression and low mutational load benefited from ipilimumab.

Of the 21 tumor samples from patients treated with the anti-PD1 antibodies pembrolizumab (Merck's Keytruda) and nivolumab (Bristol Myers-Squibb's Opdivo), six out of eight cases with high immunoproteasome subunit expression and high mutational load in tumors had a durable clinical benefit from the therapy. Meanwhile, three out of seven patients with low immunoproteasome subunit expression and low mutational load benefited from pembrolizumab or nivolumab.

Further, the team confirmed that the expression levels of the immunoproteasome subunit correlated with immune checkpoint therapy response even when mutational load, tumor purity, interferon gamma, T-cell infiltration, and CD8-positive T-cell abundance were controlled for.

They concluded that "the insights gathered through these analyses suggest that the expression levels of immunoproteasome subunits PSMB8 and PSMB9, [especially in combination with tumor mutational load], can serve as biomarkers for predicting survival of melanoma patients and for identifying patients likely to favorably respond to immune-checkpoint inhibitors."