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Myeloid Cell–associated Resistance to PD-1/PD-L1 Blockade in Urothelial Cancer Revealed Through Bulk and Single-cell RNA Sequencing

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 (Msc2IR) score. Single myeloid phagocytic cells with low Msc2IR 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.

Li Wang,1,2,3 John P. Sfakianos,4 Kristin G. Beaumont,1,2 Guray Akturk,5 Amir Horowitz,5 Robert P. Sebra,1,2,3,6 Adam M. Farkas,5 Sacha Gnjatic,5 Austin Hake,1,2 Sudeh Izadmehr,7 Peter Wiklund,4 William K. Oh,7 Peter M. Szabo,8 Megan Wind-Rotolo,8 Keziban Unsal-Kacmaz,8 Xin Yao,9 Eric Schadt,1,2,3 Padmanee Sharma,10 Nina Bhardwaj,5,7 Jun Zhu,1,2,3 and Matthew D. Galsky7

  1. Icahn Institute for Data Science and Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, New York.
  2. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  3. Sema4, a Mount Sinai venture, Stamford, Connecticut.
  4. Department of Urology, 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. Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  7. Division of Hematology Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, New York.
  8. Bristol-Myers Squibb, Princeton, New Jersey.
  9. 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.
  10. Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas

Source: Wang L, Sfakianos J, Beaumont K et al. "Myeloid Cell–associated Resistance to PD-1/PD-L1 Blockade in Urothelial Cancer Revealed Through Bulk and Single-cell RNA Sequencing."
Clin Cancer Res April 9 2021 DOI: 10.1158/1078-0432.CCR-20-4574.