Polygenic Risk for Skin Autoimmunity Impacts Immune Checkpoint Blockade in Bladder Cancer

Khan, Z.; Di Nucci, F.; Kwan, A.; Hammer, C.; Mariathasan, S.; Rouilly, V.; Carroll, J.; Fontes, M.; Ley Acosta, S.; Guardino, E.; Chen-Harris, H.; Bhangale, T.; Mellman, I.; Rosenberg, J.; Powles, T.; Hunkapiller, J.; Chandler, G. S.; Albert, M.

doi:10.1101/2019.12.18.881805

bioRxiv · 10.1101/2019.12.18.881805

Polygenic Risk for Skin Autoimmunity Impacts Immune Checkpoint Blockade in Bladder Cancer

Khan, Z.·Di Nucci, F.·Kwan, A.·Hammer, C.·Mariathasan, S.·Rouilly, V.·Carroll, J.·Fontes, M.·Ley Acosta, S.·Guardino, E.·Chen-Harris, H.·Bhangale, T.·Mellman, I.·Rosenberg, J.·Powles, T.·Hunkapiller, J.·Chandler, G. S.·Albert, M.

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Abstract

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.

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Khan, Z., Di Nucci, F., Kwan, A., Hammer, C., Mariathasan, S., Rouilly, V., Carroll, J., Fontes, M., Ley Acosta, S., Guardino, E., Chen-Harris, H., Bhangale, T., Mellman, I., Rosenberg, J., Powles, T., Hunkapiller, J., Chandler, G. S., Albert, M.. 2019-12-19. Polygenic Risk for Skin Autoimmunity Impacts Immune Checkpoint Blockade in Bladder Cancer. https://doi.org/10.1101/2019.12.18.881805

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