Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy

Abstract

INTRODUCTION Aneuploidy, also known as somatic copy number alterations (SCNAs), is widespread in human cancers and has been proposed to drive tumorigenesis. The relationship between SCNAs and the characteristic functional features or “hallmarks” of cancer is not well understood. Among these cancer hallmarks is immune evasion, which is accomplished by neoantigen editing, defects in antigen presentation and inhibition of tumor infiltration, and/or cytotoxic activities of immune cells. Whether and how tumor SCNA levels influence immune evasion is of particular interest as this information could potentially be used to improve the efficacy of immune checkpoint blockade, a therapy that has produced durable responses in a subset of cancer patients. RATIONALE Understanding how SCNAs and mutation load affect tumor evolution, and through what mechanisms, is a key objective in cancer research. To explore the relationships between SCNA levels, tumor mutations, and cancer hallmarks, we examined data from 5255 tumor/normal samples representing 12 cancer types from The Cancer Genome Atlas project. We assigned each tumor an SCNA score and looked for correlations with the number and types of tumor mutations. We also compared the gene expression profiles of tumors with high versus low SCNA levels to identify differences in cellular signaling pathways. RESULTS First, we found that, for most tumors, there was a positive correlation between SCNA levels and the total number of mutations. Second, tumors harboring activating oncogenic mutations in the receptor tyrosine kinase–RAS–phosphatidylinositol 3-kinase pathway showed fewer SCNAs, a finding at odds with the hypothesis of oncogene-driven genomic instability. Third, we found that tumors with high levels of SCNAs showed elevated expression of cell cycle and cell proliferation markers (cell cycle signature) and reduced expression of markers for cytotoxic immune cell infiltrates (immune signature). The increased expression level of the cell cycle signature was primarily predicted by focal SCNAs, with a lesser contribution of arm and whole-chromosome SCNAs. In contrast, the lower expression level of the immune signature was primarily predicted by high levels of arm and whole-chromosome SCNAs. SCNA levels were a stronger predictor of markers of cytotoxic immune cell infiltration than tumor mutational load. Finally, through analysis of data from two published clinical trials of immunotherapy in melanoma patients, we found that high SCNA levels in tumors correlated with poorer survival of patients. The combination of the tumor SCNA score and the tumor mutational load was a better predictor of survival after immunotherapy than either biomarker alone. CONCLUSION We found that two hallmarks of cancer, cell proliferation and immune evasion, are predicted by distinct types of aneuploidy that likely act through distinct mechanisms. Proliferation markers mainly correlated with focal SCNAs, implying a mechanism related to the action of specific genes targeted by these SCNAs. Immune evasion...

A B cell-derived gene expression signature associates with an immunologically active tumor microenvironment and response to immune checkpoint blockade therapy

“…Despite the small sample sizes in our study, our signature was reproducibly associated with response in both datasets targeting the PD-1/PD-L1 axis and a meta-analysis pooling the datasets revealed highly significant associations. Furthermore, while our signature was associated with response in all three datasets, many previously reported genomic-based biomarkers were not robust to the smaller sample size, including SCNA level in anti-CTLA-4 15 and mutation burden in anti-PD-1. 12 These findings suggest that the MBL signature would perform well in more highly powered studies.…”

“…Additionally, the anti-CTLA-4 dataset models included SCNA level which has been shown to associate with treatment response in a previous study. 15 In both the anti-PD-L1 and anti-PD-1 datasets, the MBL score was the only biomarker predictive of response at the univariate level (Supplementary Table S2) and remained so even after adjusting for the covariates in the multivariate model (P = 0.04 and 0.03, respectively; Table 1). Similarly, in the anti-CTLA-4 dataset, the MBL score was the only variable predictive of response in the univariate model and remained predictive in the multivariate model (P = 0.02; Table 1).…”

“…These results differed from the study that showed SCNA level was associated with response to anti-CTLA-4 therapy using many of the same samples. 15 However, this study was performed on a larger cohort of samples for which genomic data was available (n = 110), making it more highly powered to observe these associations.…”

“…10–14 Interestingly, somatic copy number alterations (SCNAs) have been shown to be more strongly correlated with tumor immune activity and response to anti-CTLA-4 than TMB, with lower SCNA levels associated with higher immune activity and improved response rates. 15 The pre-treatment transcriptome of patients receiving immune checkpoint inhibitors is one area that has yet to be fully explored. Recent studies have released transcriptomic data and identified expression-based correlates of response for small cohorts of patients receiving immune checkpoint blockade therapy.…”

New Perspectives in Medical Oncology : Molecular Medicine and its Perspectives

“…Ceci rend la comparaison des résultats de toutes ces études parfois difficile, mais cet effort de déchiffrage est important et permet d'identifier des succès importants (adénocarcinome du poumon, maladie d'Erdheim-Chester, leucémie à tricholeucocytes et inhibiteurs de BRAF, PVNS et inhibiteurs CSF1R…). Ces études pourraient en outre permettre de mieux sélectionner les candidats à l'immunothérapie anti points de contrôle immunologiques (29). Les études de prochaine génération permettront de mieux définir les objectifs et les méthodologies de ces essais (30,31).…”