Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer

PD-1 and PD-L1 act to restrict T cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs ha...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2020-06, Vol.117 (22), p.12288-12294
Hauptverfasser: Khan, Zia, Di Nucci, Flavia, Kwan, Antonia, Hammer, Christian, Mariathasan, Sanjeev, Rouilly, Vincent, Carroll, Jonathan, Fontes, Magnus, Acosta, Sergio Ley, Guardino, Ellie, Chen-Harris, Haiyin, Bhangale, Tushar, Mellman, Ira, Rosenberg, Jonathan, Powles, Thomas, Hunkapiller, Julie, Chandler, G. Scott, Albert, Matthew L.
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Sprache:eng
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Zusammenfassung:PD-1 and PD-L1 act to restrict T cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival (OS) following anti–PD-(L)1 therapy, but the factors that contribute to this relationship are poorly understood. We collected germline whole-genome sequencing data from IMvigor211, a recent phase 3 randomized controlled trial comparing atezolizumab (anti–PD-L1) monotherapy to chemotherapy in bladder cancer. We found that high vitiligo, high psoriasis, and low atopic dermatitis polygenic risk scores (PRSs) were associated with longer OS under anti–PD-L1 monotherapy as compared to chemotherapy, reflecting the Th17 polarization of these diseases. PRSs were not correlated with tumor mutation burden, PD-L1 immunohistochemistry, nor T-effector gene signatures. Shared genetic factors impact risk for dermatological autoimmunity and anti–PD-L1 monotherapy in bladder cancer.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1922867117