Journal Article

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

Khan, Zia, Fontes, Magnus, Rouilly, Vincent, Di Nucci, Flavia, Kwan, Antonia, Mariathasan, Sanjeev, Acosta, Sergio Ley, Bhangale, Tushar, Guardino, Ellie, Hammer, Christian, Rosenberg, Jonathan, Chandler, G. Scott, Chen-Harris, Haiyin, Mellman, Ira, Carroll, Jonathan, Hunkapiller, Julie, Albert, Matthew L., Powles, Thomas

2020

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Antibodies, Monoclonal, Humanized - administration & dosage / Atopic dermatitis / Autoimmunity / B7-H1 Antigen - genetics / B7-H1 Antigen - immunology / Biological Sciences / Bladder / Bladder cancer / Cancer / Chemotherapy / Cohort Studies / Dermatitis / Gene sequencing / Genetic factors / Genomes / Helper cells / Humans / Immune checkpoint / Immunohistochemistry / Immunological tolerance / Immunology and Inflammation / Lymphocytes / Lymphocytes T / Monoclonal antibodies / Multifactorial Inheritance / Mutation / PD-1 protein / PD-L1 protein / Programmed Cell Death 1 Receptor - genetics / Programmed Cell Death 1 Receptor - immunology / Psoriasis / Risk / Skin - drug effects / Skin - immunology / Skin diseases / Targeted cancer therapy / Th17 Cells - immunology / Urinary Bladder Neoplasms - drug therapy / Urinary Bladder Neoplasms - genetics / Urinary Bladder Neoplasms - immunology / Vitiligo / Whole genome sequencing