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

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.

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Association between radiomics features of DCE-MRI and CD8+ and CD4+ TILs in advanced gastric cancer

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New insights into immune cells in cancer immunotherapy: from epigenetic modification, metabolic modulation to cell communication

“… 27 Meanwhile, the exhausted T cells and immunosuppressive macrophages exhibited enhanced interactions in urothelial carcinoma of the bladder and performed significant functions in antitumor immunotherapy. 28 Deletion of sorting nexin 9 (SNX9) in CD8+ T cells reduces the exhaustion of CD8+ T cells and enhances both T memory cell differentiation and interferon‐γ (IFNγ) secretion of adoptively transferred T cells, thereby enabling effective CAR‐T cells immunotherapy. 29 In addition, the differentiation and modulation of T(H) subpopulations as well as γδ T cells in the TIME is critical for cancer immunotherapy efficacy.…”

“…Recent studies have revealed that T cells associated with recognizing cancer‐independent antigens (“bystander T cells”) also perform important functions in cancer immunotherapy and they differ in specificity, activation state, and effector function 27 . Meanwhile, the exhausted T cells and immunosuppressive macrophages exhibited enhanced interactions in urothelial carcinoma of the bladder and performed significant functions in antitumor immunotherapy 28 . Deletion of sorting nexin 9 (SNX9) in CD8+ T cells reduces the exhaustion of CD8+ T cells and enhances both T memory cell differentiation and interferon‐γ (IFNγ) secretion of adoptively transferred T cells, thereby enabling effective CAR‐T cells immunotherapy 29 .…”