Tumor aneuploidy linked to immunotherapy response
medwireNews: US researchers suggest that tumor aneuploidy could be a useful marker for response to immune checkpoint blockade in patients with cancer.
They explain that aneuploidy, defined as the presence of an abnormal number of chromosomes, and other somatic copy-number alterations (SCNAs), involving repetitions of sections of the genome, are present in the large majority of solid tumors and are hypothesized to drive the tumorigenic process.
In the current study, the team used data from a clinical trial assessing CTLA-4 inhibition in 110 patients with metastatic melanoma and found that tumor SCNA levels were significantly higher among participants who did not achieve long-term survival after treatment than in those who did.
And when patients were stratified into two groups based on the degree of tumor SCNAs, those with SCNA levels higher versus lower than the median had a significant 2.24-fold increased risk for death. By contrast, a high mutational load – a previously identified marker of immunotherapy response – was associated with improved survival (hazard ratio=0.68).
Combining the parameters to generate a risk score further improved survival prediction, such that individuals with a high score had a significant 2.51-fold higher mortality risk than their counterparts with low scores.
The results were similar when the risk score was applied to data from another clinical trial of CTLA-4 blockade in 64 melanoma patients, the team reports in Science.
Of note, an analysis of 5255 tumor and normal specimens representing 12 cancer types, derived from The Cancer Genome Atlas, showed that tumors with high levels of SCNAs (higher than the 70th percentile) had a significantly reduced expression of gene signatures associated with the immune response relative to tumors with low SCNA levels (lower than 30th percentile).
“Because the genes comprising these signatures are predominantly expressed in immune cells and not tumor cells, this observation reflects the degree of infiltration and potential activity by the immune cells in the tumor microenvironment,” write Stephen Elledge (Harvard Medical School, Boston, Massachusetts) and colleagues.
They say that “understanding the mechanism by which aneuploidy affects immune cell infiltration and responses to checkpoint blockade may provide an avenue for therapeutic intervention that could improve the efficacy of current checkpoint blockade immunotherapies.”
Describing the results as “paradigm shifting” in a related perspective, Maurizio Zanetti (University of California, San Diego, La Jolla, USA), comments that “because immune checkpoint blockade works in certain tumor types only, and tumor types vary with respect to the number of somatic mutations, assessing the level of aneuploidy can be more generally informative for predicting the status of local tumor immunity, which may be relevant to other forms of immunotherapy as well.”
He continues: “The interplay between chromosomal abnormalities and immune surveillance is now being recognized as an important new frontier in basic and applied cancer research, and a systematic genomic analysis of patient tumors may need to become a routine assessment.”
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