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GABA promotes resistance to immunotherapy of patients with TLS-positive tumours [RNA-seq]

ABSTRACT: Tertiary lymphoid structures (TLS) in the tumour microenvironment have been linked to positive clinical outcomes and responses to immune checkpoint inhibitors (ICI) in various cancers, including clear cell renal cell carcinoma (ccRCC) and soft tissue sarcoma (STS). However, a significant proportion of patients do not respond to ICI despite the presence of TLS. Our study unravels gamma-aminobutyric acid (GABA), a neurotransmission inhibitor, as a modulator of ICI resistance in TLS-positive tumours. By leveraging household and public multi-omic data, we demonstrated that GABA is upregulated in TLS-positive ccRCC and STS tumours from non-responders to ICI. In metastatic ccRCC, TLS from non-responders were distinguished from responders by a dysfunctional immune activation and a close proximity to GABA-producing proximal tubule-like tumour cells. The addition of a competitive inhibitor of GABA synthesis, 3-mercaptopropionic acid, significantly improved tumour control when compared to anti-PD1 alone when intra-tumourally injected in a mouse model of STS. Overall, our findings highlight GABA as a novel determinant of non-response to ICI in tumours harboring TLS, suggesting potential new approaches for patient stratification and personalized therapeutic strategies that could be applicable beyond metastatic ccRCC and STS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273829 | GEO | 2026/02/28

REPOSITORIES: GEO

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Project description:Background Immune checkpoint inhibitor (ICI) has greatly improved the prognosis of advanced melanoma. Whereas the efficacy in Japanese patients has been found to be lower than Caucasian, the genomic and transcriptomic features associated with response to ICI of Japanese melanomas remain to be elucidated. Patients and methods Total 129 tumour samples from 78 melanoma patients, who received therapeutic regimens with or without ICI treatment, were collected at 13 institutions in Japan. We performed exome and RNA sequencing and investigated the association of genomic and transcriptomic factors with clinical efficacy of ICI therapy. Time-course data were also analysed. This is the first and largest genomic cohort study for Japanese melanoma, in which tumour samples were prospectively analysed. Results Number of somatic SNVs of Japanese melanomas is lower than that of TCGA Caucasian data due to the biased distribution of WHO subtypes. Driver subtypes of BRAF, NRAS and NF1 was less prevalent but Triple Wildtype predominantly existed in the Japanese cohort. Whereas exome-wide survey revealed no significant association of mutated genes with ICI response, by transcriptomic analysis we identified inflammation-associated genes including several chemokines and cytokines were highly expressed in responders. Follicular helper T cells estimated by immune-cell composition analysis were found significantly enriched in responders (p = 0.0422). Through time-course transcriptome analysis, in addition to several cytotoxic T-cell genes as previously reported, MARCO on tumour-associated macrophages was found induced by ICI treatment in responders (p = 0.0040). The protein expression of these genes was confirmed by immunohistochemical and multiplex immunofluorescent analyses. Some of these genes can be useful biomarkers for prediction of ICI response in the treatment of Japanese melanoma. Conclusions Through prospective genomic and transcriptomic analyses of Japanese melanoma samples, candidate biomarkers for ICI treatment were identified.

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GABA promotes resistance to immunotherapy of patients with TLS-positive tumours [RNA-seq]

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