GABA promotes resistance to immunotherapy in patients with TLS-positive tumors.

Tertiary lymphoid structures (TLSs) correlate with favorable responses to immune checkpoint inhibitors (ICIs) in various cancers, yet many patients with TLS-positive tumors are resistant to treatment. Multi-omic profiling of clear cell renal cell carcinoma (ccRCC) and soft tissue sarcoma tumors (STSs) reveals an upregulation of gamma-aminobutyric acid (GABA)-related signatures in non-responders to ICIs. In ccRCC, TLSs from non-responders located near GABA-producing tumor cells exhibit impaired B cell maturation, reduced IgG production, higher GABA receptor expression, and tricarboxylic acid cycle activation. In vitro, exposure of human B cells to GABA reduces HLA-DR expression, proliferation, and immunoglobulin secretion by receptor-independent and dependent mechanisms. Pharmacological inhibition of GABA-synthesis increases ICI response and immune infiltration, particularly by B cells, in a TLS-positive STS mouse model. Our findings unravel GABA as an immunoregulatory metabolite and provide a rationale for its therapeutic targeting to overcome ICI resistance in patients with TLS-positive tumors.