GABA promotes resistance to immunotherapy in patients with TLS-positive tumors.
GABA-related signatures are upregulated in TLS-positive tumors from patients who do not respond to immune checkpoint inhibitors, shown in multi-omic profiling of clear cell renal cell carcinoma and soft tissue sarcoma. GABA from tumor cells impairs B cell maturation, IgG production, HLA-DR expression, proliferation and immunoglobulin secretion in vitro. Pharmacological inhibition of GABA synthesis increased ICI response and B cell infiltration in a TLS-positive sarcoma mouse model, supporting GABA targeting to overcome ICI resistance.
Why it matters: It identifies a metabolite mechanism of immune checkpoint inhibitor resistance in TLS-positive tumors and a druggable target.