Tumor-myeloid crosstalk drives therapy resistance in localized bladder cancer

Area of Science:

• Oncology
• Cancer Immunology
• Genomics

Background:

• Neoadjuvant cisplatin chemotherapy offers limited pathologic complete response rates in muscle-invasive bladder cancer (MIBC).
• Mechanisms driving chemotherapy resistance and the impact of chemotherapy on the tumor microenvironment in MIBC are not fully understood.

Purpose of the Study:

• To investigate the cellular and molecular mechanisms underlying cisplatin resistance in muscle-invasive bladder cancer.
• To identify potential therapeutic targets for overcoming chemotherapy resistance in MIBC.

Main Methods:

• Single-cell and spatial transcriptomic analysis of cancer and immune cells from MIBC patients with extreme responses to cisplatin-based chemotherapy.
• Analysis of epithelial-to-mesenchymal transition (EMT) programs in resistant cancer cells.
• Investigation of macrophage infiltration and gene expression (PARP14) in tumor niches.
• Functional studies involving PARP14 inhibition in macrophages to assess tumor sensitization to cisplatin.

Main Results:

• Persistent MIBC after chemotherapy showed cancer cells with activated epithelial-to-mesenchymal programs, correlating with worse survival.
• Cisplatin-resistant tumors were infiltrated by macrophages expressing tumor-permissive programs, characterized by elevated PARP14.
• PARP14 inhibition in macrophages reprogrammed them, downregulating pro-resistance pathways in cancer cells and sensitizing tumors to cisplatin.

Conclusions:

• Cancer cells and macrophages collaboratively promote cisplatin resistance in muscle-invasive bladder cancer.
• Macrophage-associated PARP14 is a key mediator of cisplatin resistance.
• Targeting macrophage PARP14 represents a promising therapeutic strategy to enhance cisplatin efficacy in MIBC.