Using tumor RNA samples harvested prior to immune checkpoint blockade (ICB) therapy in urothelial cancer studies, Wang et al. described an adaptive antitumor immune response gene signature associated with response, and a second signature, prominently expressed in myeloid phagocytic cells, associated with ICB resistance. The ratio between these two signatures was more strongly associated with clinical response than either signature alone. Individual myeloid cells, both in tumors and in blood, varied with respect to expression levels of the pro-tumor signature. Blood myeloid cells with a pro-tumorigenic skew were enriched in ICB-resistant patients.
Contributed by Margot O’Toole
PURPOSE: To define dominant molecular and cellular features associated with PD-1/PD-L1 blockade resistance in metastatic urothelial cancer. EXPERIMENTAL DESIGN: We pursued an unbiased approach using bulk RNA sequencing data from two clinical trials to discover (IMvigor 210) and validate (CheckMate 275) pretreatment molecular features associated with resistance to PD-1/PD-L1 blockade in metastatic urothelial cancer. We then generated single-cell RNA sequencing (scRNA-seq) data from muscle-invasive bladder cancer specimens to dissect the cellular composition underlying the identified gene signatures. RESULTS: We identified an adaptive immune response gene signature associated with response and a protumorigenic inflammation gene signature associated with resistance to PD-1/PD-L1 blockade. The adaptive immune response:protumorigenic inflammation signature expression ratio, coined the 2IR score, best correlated with clinical outcomes, and was externally validated. Mapping these bulk gene signatures onto scRNA-seq data uncovered their underlying cellular diversity, with prominent expression of the protumorigenic inflammation signature by myeloid phagocytic cells. However, heterogeneity in expression of adaptive immune and protumorigenic inflammation genes was observed among single myeloid phagocytic cells, quantified as the myeloid single cell immune:protumorigenic inflammation ratio (M(sc)2IR) score. Single myeloid phagocytic cells with low M(sc)2IR scores demonstrated upregulation of proinflammatory cytokines/chemokines and downregulation of antigen presentation genes, were unrelated to M1 versus M2 polarization, and were enriched in pretreatment blood samples from patients with PD-L1 blockade-resistant metastatic urothelial cancer. CONCLUSIONS: The balance of adaptive immunity and protumorigenic inflammation in individual tumor microenvironments is associated with PD-1/PD-L1 resistance in urothelial cancer with the latter linked to a proinflammatory cellular state of myeloid phagocytic cells detectable in tumor and blood.
Author Info: (1) Icahn Institute for Data Science and Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Genetics and Genomic Sciences, Icahn School
Author Info: (1) Icahn Institute for Data Science and Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Sema4, a Mount Sinai venture, Stamford, Connecticut. (2) Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York. (3) Icahn Institute for Data Science and Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. (4) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (5) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (6) Icahn Institute for Data Science and Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Sema4, a Mount Sinai venture, Stamford, Connecticut. Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (7) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (8) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (9) Icahn Institute for Data Science and Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. (10) Division of Hematology Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, New York. (11) Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York. (12) Division of Hematology Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, New York. (13) Bristol-Myers Squibb, Princeton, New Jersey. (14) Bristol-Myers Squibb, Princeton, New Jersey. (15) Bristol-Myers Squibb, Princeton, New Jersey. (16) Department of Genitourinary Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P.R. China. (17) Icahn Institute for Data Science and Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Sema4, a Mount Sinai venture, Stamford, Connecticut. (18) Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. (19) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. matthew.galsky@mssm.edu jun.zhu@mssm.edu Nina.bhardwaj@mssm.edu. Division of Hematology Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, New York. (20) Icahn Institute for Data Science and Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, New York. matthew.galsky@mssm.edu jun.zhu@mssm.edu Nina.bhardwaj@mssm.edu. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Sema4, a Mount Sinai venture, Stamford, Connecticut. (21) Division of Hematology Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, New York. matthew.galsky@mssm.edu jun.zhu@mssm.edu Nina.bhardwaj@mssm.edu.
