TCR-Vγδ usage distinguishes protumor from antitumor intestinal γδ T cell subsets

Area of Science:

• Immunology
• Oncology
• Gastroenterology

Background:

• Gamma delta (γδ) T cells are abundant in the gut lining during homeostasis.
• These cells are also found in colorectal cancers (CRCs), but their specific roles in cancer development are not fully understood.

Purpose of the Study:

• To investigate the temporal roles of γδ T cells in colorectal cancer (CRC) development and progression.
• To understand how γδ T cell functions change from premalignant stages to established tumors.

Main Methods:

• Analysis of human CRC samples and murine CRC models.
• Characterization of γδ T cell markers and T cell receptor (TCR)-Vγδ gene usage.
• Utilizing longitudinal intersectional genetics and antibody-dependent strategies in mice.

Main Results:

• Premalignant/nontumor colonic γδ T cells displayed cytotoxic markers, while tumor-infiltrating γδ T cells showed a protumorigenic profile.
• Distinct TCR-Vγδ gene usage correlated with these differing γδ T cell phenotypes.
• Targeting steady-state epithelial γδ T cells exacerbated tumor development.
• Targeting CRC-accumulated γδ T cell subsets reduced tumor growth.

Conclusions:

• γδ T cells exhibit dynamic, context-dependent roles in CRC.
• Early-stage γδ T cells may have antitumor functions, while later-stage tumor-associated γδ T cells can promote CRC progression.