Germline variants that influence the tumor immune microenvironment also drive response to immunotherapy

Pagadala, M.; Wu, V. H.; Perez-Guijarro, E.; Kim, H.; Castro, A.; Talwar, J.; Gonzalez-Colin, C.; Cao, S.; Schmiedel, B.; Salem, R.; Morris, G.; Harismendy, O.; Patel, S. P.; Mesirov, J. P.; Zanetti, M.; Day, C.-P.; Fan, C. C.; Thompson, W. K.; Merlino, G.; Gutkind, J. S.; Vijayanand, P.; Carter, H.

doi:10.1101/2021.04.14.436660

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bioRxiv · 10.1101/2021.04.14.436660

Germline variants that influence the tumor immune microenvironment also drive response to immunotherapy

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Abstract

With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Approaches that intersect SNP modifiers of molecular phenotype, such as gene expression, with disease phenotypes have shown promise for implicating causal genetic factors. Here we evaluated 194 literature-curated TIME associations and 890 associations detected with 157 immune phenotype (IP) components found using genotypes from over 8,000 individuals in The Cancer Genome Atlas. Of these 1084, 233 associations comprising 219 unique TIME-SNPs were also cancer relevant, associating with cancer risk, survival, and/or immunotherapy treatment response. Many cancer relevant TIME-SNPS overlapped regions of active transcription, and were associated with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. TIME-SNPs associated with cancer risk and response to immunotherapy implicated genes involved in antigen presentation, especially by antigen presenting cells. The strongest associations with survival were with PD-L1 and CTLA-4, suggesting that SNPs modifying the potential for immune evasion could contribute to disease progression. To assess whether our approach could reveal novel cancer immunotherapy targets, we inhibited CTSS, a gene implicated by cancer risk and immunotherapy response-associated TIME-SNPs; CTSS inhibition resulted in slowed tumor growth and extended survival in vivo. These results validate the potential of cancer relevant TIME-SNPs to implicate target genes for countering immune suppressive characteristics of the TIME and set the stage for future host genetics analysis integrating germline variation and TIME characteristics. SignificanceA systematic screen for common germline variants associated with the tumor immune microenvironment across > 8000 tumors reveals novel cancer risk factors and targets for immunotherapy.

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Pagadala, M., Wu, V. H., Perez-Guijarro, E., Kim, H., Castro, A., Talwar, J., Gonzalez-Colin, C., Cao, S., Schmiedel, B., Salem, R., Morris, G., Harismendy, O., Patel, S. P., Mesirov, J. P., Zanetti, M., Day, C.-P., Fan, C. C., Thompson, W. K., Merlino, G., Gutkind, J. S., Vijayanand, P., Carter, H.. 2021-04-15. Germline variants that influence the tumor immune microenvironment also drive response to immunotherapy. https://doi.org/10.1101/2021.04.14.436660

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