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Checkpoint Blockade Response Shows Ties to Metabolic Gene Expression in Kidney Cancer Patients

NEW YORK (GenomeWeb) – In a study appearing online today in Cancer Immunology Research, investigators at Johns Hopkins University School of Medicine described differences in metabolic gene expression that coincided with response to Bristol-Myers Squibb's anti-PD-1 drug Opdivo (nivolumab) in individuals with PD-L1-positive renal cell carcinoma (RCC) kidney cancers.

The team did array-based gene expression profiling on tumor samples from 11 individuals with metastatic RCC, focusing on tumor sites that express the PD-L1 protein — one of several proposed markers for response to anti-PD-1 treatments.

When they searched for gene expression differences between tumors from the four individuals who responded to nivolumab and the seven who did not, the researchers saw 110 genes with elevated expression in the nivolumab non-responders — many of which belonged to metabolism- and solute transport-related pathways.

"If these data are reproduced in larger groups of patients, we could potentially use the information to guide treatment decisions for patients with renal cell carcinoma," senior author Suzanne Topalian, director of the Sidney Kimmel Comprehensive Cancer Center's melanoma program and associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, said in a statement.

In prior studies of advanced RCC, about 15 to 30 percent of patients have shown robust and lasting responses to immunotherapy treatments such as nivolumab that target the PD-1/PD-L1 immune checkpoint, the team noted. Although PD-L1 expression in tumors and tumor infiltrating immune cells has been linked to enhanced anti-PD-1 treatment response, the researchers reasoned that additional markers for response might be found through further comparisons of nivolumab responders and non-responders.

"[A] significant number of patients with PD-L1-positive RCC do not respond to PD-1 pathway blockade," they wrote, "suggesting that additional intra-tumoral factors may influence treatment outcomes."

The researchers did not uncover any differences in immune-related gene expression in RCC patients with PD-L1-positive tumors who did or did not respond to anti-PD-1 treatment, either by multiplex quantitative RT-PCR or by immunohistochemistry. So they moved on to Illumina human expression arrays to assess genome-wide expression patterns in tumor samples from 11 patients with PD-L1-positive RCCs who were being treated through one of four clinical trials at the Johns Hopkins Kimmel Cancer Center: four anti-PD-1 treatment responders and seven non-responders.

That analysis pointed to altered expression at more than 200 genes, depending on treatment outcome, including 113 genes with higher-than-usual expression in tumor samples from RCC patient who did respond to nivolumab and 110 genes with elevated expression in the tumors from nivolumab non-responders.

While some immune-related genes were among those dialed up in the responders' tumor samples, the team found that metabolism-related genes were more likely to show expression jumps in the tumor samples from non-responders — results that were subsequently verified by quantitative RT-PCR.

In contrast, the researchers did not see ties between survival outcomes for RCC patients and general tumor expression of one of the metabolic genes, UGT1A6, in data from 444 primary clear cell RCC samples tested for the Cancer Genome Atlas, suggesting the effect may be specific to checkpoint blockade-based treatment response rather than tumor aggressiveness.

"Given that nivolumab works by releasing the brakes on the immune system, most studies of treatment resistance so far have focused on looking for immune system-related mechanisms," Topalian said. "Our data suggest that resistance can also be caused by tumor-specific mechanisms."

She and her team said they plan to verify their current findings in larger studies of anti-PD-1-treated RCC patients and to take the same transcriptomic approach forward to find clues to immune checkpoint blockade response in other cancer types.

"Despite the limitations inherent to this retrospective study of a small number of specimens, the significantly differential gene expression profiles described here provide a basis for future exploration in larger RCC cohorts, potentially including [PD-L1-positive and –negative] tumors," the study's authors wrote. "A deeper level of investigation may be warranted for individual tumor types, and intersections of tumor cell-intrinsic factors with immunologic factors may be particularly revealing."

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