Targeting senescent EGR1⁺ B cells enhances immunotherapy efficacy in esophageal squamous cell carcinoma

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Neoadjuvant immune checkpoint blockade (NICB) is a standard therapy for esophageal squamous cell carcinoma (ESCC).
• Mechanisms underlying NICB failure in ESCC are not fully understood.

Purpose of the Study:

• To elucidate the cellular mechanisms contributing to NICB failure in ESCC.
• To identify predictive biomarkers for NICB response.
• To explore therapeutic strategies to overcome NICB resistance.

Main Methods:

• Single-cell RNA sequencing of ESCC patient tumors before and after NICB.
• Bioinformatic analysis to identify cell subsets and key regulatory factors.
• In vitro and in vivo validation of identified mechanisms and therapeutic targets.

Main Results:

• A subset of senescent B cells expressing EGR1 (EGR1+ B cells) was identified, correlating with poor pathological response to NICB.
• EGR1 was confirmed as a key transcription factor driving B cell senescence.
• Senescent EGR1+ B cells promote immunosuppression via SASP, inducing TREM2+ TAMs in the tumor microenvironment.
• Fisetin demonstrated potential in mitigating B cell senescence and enhancing NICB efficacy.

Conclusions:

• Senescent EGR1+ B cells are a critical mechanism of NICB failure in ESCC.
• These cells contribute to an immunosuppressive tumor microenvironment.
• Targeting B cell senescence represents a promising strategy to improve NICB outcomes in ESCC.