Single-cell and spatial transcriptomic analysis reveal cellular heterogeneity and cancer cell-intrinsic major histocompatibility complex II expression in urothelial carcinoma

TL;DR

This study uses single-cell and spatial transcriptomics to uncover immune cell dynamics and cancer cell traits in bladder cancer, revealing how tumors evade the immune system.

Contribution

The study identifies cancer cell-intrinsic MHC-II expression and its role in immune evasion during urothelial carcinoma progression.

Findings

MHC-II⁺ cancer cells are induced by interferon-γ and show increased proliferation and migration.

MHC-II⁺ cancer cells spatially interact with immune cells, promoting T cell exhaustion and immune evasion.

An immunosuppressive tumor microenvironment is observed in muscle-invasive urothelial carcinoma.

Abstract

Muscle-invasive (MI) urothelial carcinoma (UC) is a clinically challenging malignancy with a poor prognosis. Understanding the cellular dynamics that drive UC progression is critical for the development of optimized therapeutic strategies. Through integrative analysis of large-scale single-cell transcriptomic datasets from non-muscle-invasive (NMI) and MI tumours and validation with spatial transcriptomic datasets, we systematically characterized immune cell dynamics and cancer cell plasticity during UC progression. Our analysis revealed an immunosuppressive tumour microenvironment and a subset of cancer cells with upregulated major histocompatibility complex II (MHC-II) expression in MI tumours. Notably, MHC-II⁺ cancer cells were induced by interferon-γ signalling, as confirmed through in vitro experiments, and exhibited phenotypic alterations characterized by enhanced proliferative and migratory capacities. Furthermore, MHC-II⁺ cancer cells spatially colocalized with CD8⁺ T cells, regulatory T cells, and SPP1⁺ macrophages, where they engaged with inhibitory receptors on these immune cells, promoted CD8⁺ T cell exhaustion and facilitated immune evasion.

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