Intratumoral SPP1⁺BCL2A1⁺ Tumor-Associated Macrophages Predict Poor Response to PD1 Blockade

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Immune checkpoint blockade (ICB) shows promise for hepatocellular carcinoma (HCC), but predictive biomarkers are limited.
• Tumor-associated macrophages (TAMs) significantly influence the tumor immune microenvironment.
• Identifying specific TAM subsets can improve understanding of ICB resistance in HCC.

Purpose of the Study:

• To identify novel biomarkers for predicting ICB response in HCC.
• To characterize the role of TAMs in the HCC tumor microenvironment.
• To investigate SPP1 and BCL2A1 double-positive TAMs as potential prognostic indicators.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) was used to analyze intratumoral immune cells in HCC.
• Unsupervised clustering and gene signature analysis identified SPP1+BCL2A1+ TAMs.
• Independent HCC transcriptomic datasets were used to validate findings and correlate with ICB response.

Main Results:

• Elevated intratumoral SPP1+BCL2A1+ TAMs were found in HCC patients.
• High expression of these TAMs correlated with poorer response to ICB therapy.
• These TAMs were associated with immunosuppressive microenvironments in non-responders and cytotoxic T-cell responses in responders.

Conclusions:

• SPP1+BCL2A1+ TAMs serve as a poor prognostic biomarker for HCC patients receiving ICB therapy.
• These TAMs promote an immunosuppressive microenvironment, potentially explaining ICB resistance.
• SPP1+BCL2A1+ TAMs represent a potential therapeutic target to enhance immunotherapy efficacy.