A conserved intratumoral regulatory T cell signature identifies 4-1BB as a pan-cancer target

Area of Science:

• Immunology
• Oncology
• Cancer Immunotherapy

Background:

• Current cancer immunotherapies targeting PD-1, PD-L1, and CTLA-4 have limited efficacy in many patients and cancer types.
• Existing treatments primarily focus on enhancing antitumor CD8 T cell responses.
• Regulatory T cells (Tregs) can suppress anti-tumor immunity, presenting an alternative therapeutic target.

Purpose of the Study:

• To identify immune molecules specifically expressed on tumor-infiltrating Tregs.
• To explore the potential of targeting these molecules as a complementary cancer immunotherapy strategy.

Main Methods:

• Genome-wide RNA-Seq analysis of Tregs purified from various human cancers.
• Immunocompetent murine tumor models were used to test antibody-mediated depletion of 4-1BB-expressing cells.
• Analysis of 4-1BB expression in human tumor samples and correlation with survival outcomes.

Main Results:

• A conserved Treg immune checkpoint signature was identified across multiple human cancer types.
• Depletion of 4-1BB-expressing cells in murine models reduced tumor growth without impairing CD8 T cell function.
• The immune checkpoint 4-1BB demonstrated high selectivity for human tumor Tregs and was linked to poorer survival in multiple cancer types.

Conclusions:

• Antibody-mediated depletion of 4-1BB-expressing Tregs is a promising strategy for cancer immunotherapy.
• This approach may offer potential activity across a broad range of cancer types.
• Targeting 4-1BB on Tregs represents a novel avenue to overcome resistance to current immunotherapies.