Tumor-Infiltrating Myeloid Cells Confer De Novo Resistance to PD-L1 Blockade through EMT-Stromal and Tgfβ-Dependent...

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• Immune checkpoint blockade (ICB) targeting the PD-L1 signaling axis is a key treatment for many cancers.
• However, a significant number of bladder cancer patients exhibit primary resistance to PD-L1 targeted ICB.
• Understanding the mechanisms of resistance is crucial for improving therapeutic outcomes.

Purpose of the Study:

• To investigate the mechanisms underlying resistance to PD-L1 targeted ICB in bladder cancer.
• To identify novel biomarkers or therapeutic targets associated with treatment failure.

Main Methods:

• Development and application of a de novo resistance signature.
• Analysis of tumor-infiltrating myeloid cells.
• Investigation of the role of transforming growth factor beta (TGFβ) signaling.

Main Results:

• A de novo resistance signature was identified and applied to patient data.
• Tumor-infiltrating myeloid cells were found to be associated with poor response to ICB.
• A TGFβ-dependent mechanism was implicated in mediating this resistance.

Conclusions:

• Tumor-infiltrating myeloid cells contribute to resistance against PD-L1 targeted ICB in bladder cancer.
• TGFβ signaling plays a critical role in this resistance mechanism.
• Targeting myeloid cells or TGFβ may represent a viable strategy to overcome ICB resistance.