TY - JOUR T1 - Myeloid cell-associated resistance to PD-1/PD-L1 blockade in urothelial cancer revealed through bulk and single-cell RNA sequencing JF - bioRxiv DO - 10.1101/2020.09.16.300111 SP - 2020.09.16.300111 AU - Li Wang AU - John P. Sfakianos AU - Kristin G. Beaumont AU - Guray Akturk AU - Amir Horowitz AU - Robert Sebra AU - Adam M. Farkas AU - Sacha Gnjatic AU - Austin Hake AU - Sudeh Izadmehr AU - Peter Wiklund AU - William K Oh AU - Peter Szabo AU - Megan Wind-Rotolo AU - Kezi Unsal-Kacmaz AU - Xin Yao AU - Eric Schadt AU - Padmanee Sharma AU - Nina Bhardwaj AU - Jun Zhu AU - Matthew D. Galsky Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/09/17/2020.09.16.300111.abstract N2 - Adaptive immunity and tumor-promoting inflammation exist in delicate balance in individual tumor microenvironments; however, the role of this balance in defining sensitivity and resistance to PD-1/PD-L1 blockade therapy in urothelial cancer and other malignancies is poorly understood. We pursued an unbiased systems biology approach using bulk RNA sequencing data to examine pre-treatment molecular features associated with sensitivity to PD-1/PD-L1 blockade in patients with metastatic urothelial cancer and identified an adaptive_immune_response module associated with response and an inflammatory_response module and stromal module associated with resistance. We mapped these gene modules onto single-cell RNA sequencing data demonstrating the adaptive_immune_response module emanated predominantly from T, NK, and B cells, the inflammatory_response module from monocytes/macrophages, and the stromal module from fibroblasts. The adaptive_immune_response:inflammatory_response module expression ratio in individual tumors, reflecting the balance between antitumor immunity and tumor-associated inflammation and coined the 2IR score, best correlated with clinical outcomes and was validated in an independent cohort. Individual monocytes/macrophages with low 2IR scores demonstrated upregulation of proinflammatory genes including IL1B and downregulation of antigen presentation genes, were unrelated to classical M1 versus M2 polarization, and were enriched in pre-treatment peripheral blood from patients with PD-L1 blockade-resistant metastatic urothelial cancer.Single sentence summary Proinflammatory monocytes/macrophages, present in tumor and blood, are associated with resistance to immune checkpoint blockade in urothelial cancer.Competing Interest StatementMDG has served as a consultant or advisor to BioMotiv, Janssen, Dendreon, Merck, Glaxo Smith Kline, Lilly, Astellas, Genentech, Bristol-Myers Squibb, Novartis, Pfizer, EMD Serono, Astra Zeneca, Seattle Genetics, Incyte, Aileron, Dracen, Inovio, NuMab, Dragonfly Therapeutics. He has received research funding from Janssen, Dendreon, Novartis, Bristol-Myers Squibb, Merck, Astra Zeneca, Genentech/Roche. NB has served as a consultant or advisor to Neon, Tempest, Checkpoint Sciences, Curevac, Primevax, Novartis, Array BioPharma, Roche, Avidea, Boehringer Ingelheim, Rome Therapeutics, Roswell Park, Parker Institute for Cancer Immunotherapy. She has received research funding from Novocure, Ludwg Institute, Celldex, Genentech, Oncovir, Melanoma Research Alliance, Leukemia & Lymphoma Society, NSTEM, Regeneron. WKO has served as a consultant to Astellas, Astra Zeneca, Bayer, Janssen, Sanofi, Sema4 and TeneoBio. SG reports consultancy and/or advisory roles for Merck, Neon Therapeutics and OncoMed and research funding from Bristol-Myers Squibb, Genentech, Immune Design, Agenus, Janssen R&D, Pfizer, Takeda, and Regeneron. S.G. is a named co-inventor on an issued patent for multiplex immunohistochemistry to characterize tumors and treatment responses. The technology is filed through Icahn School of Medicine at Mount Sinai (ISMMS) and non-exclusively licensed to Caprion. Mount Sinai has received payments associated with this technology and Dr. Gnjatic is entitled to future payments. PS reports consultantships for Oncolytics, Jounce, BioAtla, Forty-Seven, Polaris, Marker, Codiak, ImaginAB, Hummingbird, Dragonfly, Lytix, Lava Therapeutics, Infinity and Achelois. Dr. Sharma reports ownership interests in Constellation, Oncolytics, Apricity Health, Hummingbird, Dragonfly, Lytix, Lava Therapeutics, Achelois, Jounce, Neon, BioAtla, Forty-Seven, Polaris, Marker, Codiak, and ImaginAb. PS also owns a patent licensed to Jounce. JS has served as a speaker for Pfizer. AH has served as a consultant or advisor to HTG Molecular. JZ, LW, and ES are employees of SEMA4 ER -