BCL6 promotes a stem-like CD8⁺ T cell program in cancer via antagonizing BLIMP1

Area of Science:

• Immunology
• Cancer Biology
• T cell biology

Background:

• Overcoming CD8+ T cell exhaustion is crucial for effective cancer immunotherapy.
• Intratumor CD8+ T progenitor cells (Tprog cells) sustain antitumor responses but can differentiate into terminally exhausted cells (Tterm cells).
• The extrinsic signals controlling Tprog cell persistence and differentiation remain largely unknown.

Purpose of the Study:

• To investigate the role of transcription factors, specifically BCL6, in regulating CD8+ T cell differentiation and persistence within the tumor microenvironment.
• To elucidate the signaling pathways controlling Tprog cell fate and their impact on antitumor immunity and immunotherapy efficacy.

Main Methods:

• Analysis of BCL6 expression in tumor-specific CD8+ T cells in draining lymph nodes and tumors.
• Investigated the effects of BCL6 deficiency on Tprog cell persistence and tumor control.
• Examined the regulatory roles of TGF-β-SMAD2 and IL-2-STAT5 signaling pathways on BCL6 and BLIMP1 expression.
• Assessed the impact of PRDM1 (BLIMP1) deficiency on Tprog cell program and anti-PD-1 therapy efficacy.

Main Results:

• BCL6 inhibits the generation of tumor-specific Tterm cells from Tprog cells, downstream of TCF1.
• Bcl6 deficiency reduced Tprog cell persistence, impairing long-term tumor control.
• BCL6 expression is upregulated by TGF-β-SMAD2 signaling and downregulated by IL-2-STAT5 signaling, acting antagonistically to BLIMP1.
• PRDM1 deficiency promoted the Tprog cell program and enhanced anti-PD-1 therapy efficacy.

Conclusions:

• The TGF-β-BCL6 and IL-2-BLIMP1 signaling pathways antagonistically regulate antitumor CD8+ T cell differentiation and function.
• Targeting these pathways, particularly by modulating BCL6 activity, holds promise for developing more effective and long-lasting cancer immunotherapies.