Abstract
Tumors with high copy number alteration (CNA) burden often respond poorly to immune checkpoint inhibitor therapy. However, how CNAs affect the anti-cancer immune response remains unclear. To address this, we set out to capture the transcriptional effects of CNAs and define a comprehensive landscape of immune-related transcriptional patterns. Hereto, we applied consensus independent component analysis to 294,159 bulk transcriptomic profiles. We demonstrated the predictive power of these patterns for immunotherapy response, their reproducibility across platforms, and their applicability to bulk, single-cell, and spatial transcriptomic data. Our analysis identified both novel inverse and positive associations between high CNA burden and immune-related transcriptional patterns across various cancer types. For example, higher CNA burden correlated with increased immunosuppression, including IL-17-producing cells and regulatory T cells. This resource, along with the classification of these transcriptional patterns as immune-suppressive and immune-stimulatory, may provide insights to improve immunotherapy efficacy in tumors with high CNA burden.
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Data availability
The CNA-immune associations can be explored at http://cna-immune.opendatainscience.net. All data, results, and codes generated as part of this study are available at https://zenodo.org/records/17715512. Gene expression data were collected from three public data repositories: Gene Expression Omnibus with accession number GPL570 generated with microarray Affymetrix HG-U133 Plus 2.0 (https://www.ncbi.nlm.nih.gov/geo/), ARCHS4 RNA-seq from human version v1.10 (https://maayanlab.cloud/archs4/download.html), and TCGA RNA-seq data from the Broad GDAC Firehose portal (https://gdac.broadinstitute.org/). ICI response datasets were obtained from the referenced studies. Single-cell RNA-seq data were obtained from the single-cell tumor immune atlas for precision oncology (https://zenodo.org/records/5205544). Spatial transcriptomic profiles were obtained from the 10x Genomics website (https://www.10xgenomics.com).
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Acknowledgements
This work was supported by a grant from the Hanarth Fund to R.S.N.F., and by a KWF Kankerbestrijding grant [grant number KWF-14516] awarded to M.A.T.M.v.V. and R.S.N.F.
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R.S.N.F. conceived and designed this study. S.L., A.B., C.G.U.-T., and R.S.N.F. collected and assembled data and performed data analyses. S.L. and C.G.U.-T. developed the figures used in this study. S.L., A.B., C.G.U.-T., M.A.T.M.v.V., M.d.B., and R.S.N.F. contributed to the data interpretation, writing of the paper, and the final decision to submit the paper.
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M.d.B. received grants from the Dutch Cancer Society (KWF), the European Research Council (ERC), Health Holland (HH), Mendus, BioNovion, Aduro Biotech, Vicinivax, Genmab, and IMMIOS (all paid to the institute); received non-financial support from BioNTech, Surflay Nanotec, and Merck Sharp & Dohme; is a stock option holder in Sairopa; all unrelated to the submitted work. The remaining authors declare no competing interests.
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Loipfinger, S., Bhattacharya, A., Urzúa-Traslaviña, C.G. et al. Association of copy number alterations with the immune transcriptomic landscape in cancer. npj Syst Biol Appl (2026). https://doi.org/10.1038/s41540-026-00649-8
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DOI: https://doi.org/10.1038/s41540-026-00649-8
