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Theranostics 2022; 12(18):7745-7759. doi:10.7150/thno.77281 This issue Cite

Research Paper

Single-cell atlases link macrophages and CD8+ T-cell subpopulations to disease progression and immunotherapy response in urothelial carcinoma

Yuan Liang1*, Yezhen Tan1,3*, Bao Guan2,4*, Bin Guo1,3, Mancheng Xia2,4, Juan Li1,3, Yue Shi1, Zihui Yu1,3, Qi Zhang1,3, Di Liu5, Xiaopeng Yang5, Junfeng Hao5, Yanqing Gong2,4,6, Muhammad Shakeel7, Liqun Zhou2,4,6✉, Weimin Ci1,3,8✉, Xuesong Li2,4,6✉

1. CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China.
2. Department of Urology, Peking University First Hospital, Beijing 100034, China.
3. University of Chinese Academy of Sciences, Beijing 100049, China.
4. Institute of Urology, Peking University, Beijing 100034, China.
5. Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
6. National Urological Cancer Center, Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China.
7. Jamil-ur-Rahman Center for Genome Research, Dr. Panjwani Center for Molecular Medicine and Drug Research, ICCBS, University of Karachi, Karachi, Pakistan.
8. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Department of Urology, Peking University First Hospital; Institute of Urology, Peking University. No.8, Street Xishiku, District Xicheng, Beijing 100034, China. Tel: +86-10-8357-2211. E-mail addresses: pineneedlecom (X. More

Citation:
Liang Y, Tan Y, Guan B, Guo B, Xia M, Li J, Shi Y, Yu Z, Zhang Q, Liu D, Yang X, Hao J, Gong Y, Shakeel M, Zhou L, Ci W, Li X. Single-cell atlases link macrophages and CD8+ T-cell subpopulations to disease progression and immunotherapy response in urothelial carcinoma. Theranostics 2022; 12(18):7745-7759. doi:10.7150/thno.77281. https://www.thno.org/v12p7745.htm
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Abstract

Graphic abstract

Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized the management of locally advanced or metastatic urothelial carcinoma. Strikingly, compared to urothelial carcinoma of the bladder (UCB), upper tract urothelial carcinoma (UTUC) has a higher response rate to ICIs. The stratification of patients most likely to benefit from ICI therapy remains a major clinical challenge.

Methods: In this study, we performed the first single-cell RNA sequencing (scRNA-seq) study of 13 surgical tissue specimens from 12 patients with UTUC. The key results were validated by the analysis of two independent cohorts with bulk RNA-seq data for UCB (n = 404) and UTUC (n = 158) and one cohort of patients with metastatic urothelial carcinoma (mUC) who were treated with atezolizumab (n = 348).

Results: Using scRNA-seq, we observed a higher proportion of tumor-infiltrating immune cells in locally advanced UTUC. Similar prognostically relevant intrinsic basal and luminal-like epithelial subtypes were found in both UTUC and UCB, although UTUC is predominantly of the luminal subtype. We also discovered that immunosuppressive macrophages and exhausted T-cell subpopulations were enriched in the basal subtype and showed enhanced interactions. Furthermore, we developed a gene expression signature (Macro-C3 score) capturing the immunosuppressive macrophages that better predicts outcomes than the currently established subtypes. We also developed a computational method to model immune evasion, and the Macro-C3 score predicted therapeutic response of mUC treated with first-line anti-PD-L1 inhibitors in patients with lower basal scores.

Conclusions: Overall, the distinct microenvironment and Macro-C3 score provide an explanation for ICI efficacy in urothelial carcinoma and reveal new candidate regulators of immune evasion, suggesting potential therapeutic targets for improving antitumor immunity in the basal subtype.

Keywords: Immunosuppression, Immunotherapy, Single-cell RNA sequencing, Tumor microenvironment, Urothelial carcinoma

Citation styles

APA
Liang, Y., Tan, Y., Guan, B., Guo, B., Xia, M., Li, J., Shi, Y., Yu, Z., Zhang, Q., Liu, D., Yang, X., Hao, J., Gong, Y., Shakeel, M., Zhou, L., Ci, W., Li, X. (2022). Single-cell atlases link macrophages and CD8+ T-cell subpopulations to disease progression and immunotherapy response in urothelial carcinoma. Theranostics, 12(18), 7745-7759. https://doi.org/10.7150/thno.77281.

ACS
Liang, Y.; Tan, Y.; Guan, B.; Guo, B.; Xia, M.; Li, J.; Shi, Y.; Yu, Z.; Zhang, Q.; Liu, D.; Yang, X.; Hao, J.; Gong, Y.; Shakeel, M.; Zhou, L.; Ci, W.; Li, X. Single-cell atlases link macrophages and CD8+ T-cell subpopulations to disease progression and immunotherapy response in urothelial carcinoma. Theranostics 2022, 12 (18), 7745-7759. DOI: 10.7150/thno.77281.

NLM
Liang Y, Tan Y, Guan B, Guo B, Xia M, Li J, Shi Y, Yu Z, Zhang Q, Liu D, Yang X, Hao J, Gong Y, Shakeel M, Zhou L, Ci W, Li X. Single-cell atlases link macrophages and CD8+ T-cell subpopulations to disease progression and immunotherapy response in urothelial carcinoma. Theranostics 2022; 12(18):7745-7759. doi:10.7150/thno.77281. https://www.thno.org/v12p7745.htm

CSE
Liang Y, Tan Y, Guan B, Guo B, Xia M, Li J, Shi Y, Yu Z, Zhang Q, Liu D, Yang X, Hao J, Gong Y, Shakeel M, Zhou L, Ci W, Li X. 2022. Single-cell atlases link macrophages and CD8+ T-cell subpopulations to disease progression and immunotherapy response in urothelial carcinoma. Theranostics. 12(18):7745-7759.

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