A protective cGAMP-mediated anti-tumor immune response can proceed without LRRC8/VRAC channels

Area of Science:

• Molecular Biology
• Immunology
• Cancer Research

Background:

• The volume-regulated anion channel (VRAC), a LRRC8A-hetero-hexamer, transports chloride and organic molecules like 2'3'-cGAMP (cGAMP).
• cGAMP transfer from tumor to host cells is vital for anti-tumor immunity, but VRAC's in vivo role is unclear.

Purpose of the Study:

• To investigate the role of VRAC in cGAMP transport for anti-tumor immunity in vivo.
• To determine if tumor or host VRAC expression impacts anti-tumor immune responses and tumor growth.

Main Methods:

• Studied subcutaneous MC38 and B16-F10 tumors in syngeneic mice.
• Utilized LRRC8A-deficient tumor cells and mice with selective LRRC8 subunit disruptions.
• Assessed tumor growth, serum cytokines, and anti-tumor immune responses.

Main Results:

• MC38 tumors lacking cGAMP production showed enhanced growth, confirming cGAMP's importance.
• VRAC-mediated cGAMP export from MC38 tumors had moderate immunomodulatory effects on serum cytokines.
• Tumor growth and cGAMP-mediated anti-tumor immunity were independent of tumor- and host-expressed VRAC.
• Disruption of LRRC8B-LRRC8E subunits did not affect T or B cell development.

Conclusions:

• While tumor-produced cGAMP suppresses tumor growth, its transport to the tumor microenvironment relies on transporters other than VRAC.
• VRAC is not essential for cGAMP-mediated anti-tumor immunity in this mouse model.