Recent studies have linked elevated tumor aneuploidy, or abnormal numbers of chromosomes in cancer cells, to the suppression of anti-tumor immune responses and poorer prognosis following immunotherapy. Aneuploidy has been shown to suppress the infiltration of CD8+ T cells and natural killer cells into tumors and compromise their function. Ludwig Chicago’s Sean Pitroda and a University of Chicago colleague explored whether aneuploidy scores could serve as prognostic markers of response to immune checkpoint blockade (ICB) in patients with non-small cell lung cancer (NSCLC). Analyzing data from a 309-patient cohort in which Sean’s team linked aneuploidy to poor ICB response, they further demonstrated a novel association between elevated aneuploidy and nonsmoking-associated NSCLC oncogenic driver mutations, validating their findings in an independent cohort of 350 NSCLC patients treated with ICB. They reported in their August paper in Scientific Reports an association of high aneuploidy with immunosuppressive tumor states and focal amplifications of the TERT gene. Aneuploidy scores exhibit a dose–response relationship with objective response rate and overall survival. Further, patients with aneuploidy affecting more than half of the genome were especially unlikely to exhibit an objective response to immunotherapy. Aneuploidy’s negative effect on survival was, however, attenuated by combination anti-CTLA-4 and anti-PD-1 antibodies in comparison to single-agent therapy. Their findings underscore a potentially useful role for measures of tumor aneuploidy in guiding immunotherapy.
Clinical and molecular correlates of tumor aneuploidy in metastatic non-small cell lung cancer
Scientific Reports, 2024 August 21