Bulk RNA Sequencing of Human PDAC: TLS-Positive vs. TLS-Negative
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PROVIDER: PRJNA1152952 | ENA |
REPOSITORIES: ENA
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Project description:The formation of tertiary lymphoid structures (TLSs) in tumors is significantly correlated with prolonged patient survival, better prognosis, and improved response to immunotherapy. Understanding the tumor microenvironments involved in TLS formation is crucial. This bulk RNA sequencing study utilized archived FFPE samples from PDAC patients to reveal gene expression profiles in tumors with TLS formation.
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Project description: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.
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Project description: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.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is considered an immunologically cold cancer type. This perception is due to its rapid progression, strong presence of immunosuppressive cells and lack of response to current immunotherapies. However, we and others have shown that many patient PDAC tumors contain robust lymphocyte infiltration, aggregated in the form of tertiary lymphoid structures (TLS). The presence of TLS in PDAC is prognostic for long-term survival and in other cancer types, predictive of response to immunotherapy. Despite the clinical benefit to generating TLS in tumors, why they form in some PDAC patients but not others, remains unknown. The desmoplastic stroma in PDAC contributes to defective anti-tumor immunity largely due to myofibroblastic cancer associated fibroblasts (myCAF) induced by transforming growth factor-beta (TGF). Other groups have demonstrated that mesenchymal cell phenotypes with lymphoid tissue organizing properties regulate TLS formation in tumors. In order to restore effective anti-tumor immunity for PDAC patients, CAF phenotypes must be reprogrammed to support rather than restrict intratumoral immune activity. Using a lymphotoxin beta receptor (LTBR) agonist we observed induction of TLS-like aggregates in some murine PDAC tumor models, but not others. The CAF phenotypes of TLS-resistant models were predominantly myCAF while the TLS-permissive models were enriched for a VCAM1+ICAM1+ reticular-CAF (rCAF) subset. Induction of myCAF differentiation in vitro with TGF1 silenced LTBR/TNFR mediated upregulation of rCAF chemokine expression and attenuated B and T cell migration towards fibroblasts. Therapeutic TGFR1 inhibition ameliorated these effects thereby allowing LTBR agonism to repolarize rCAF phenotypic programming associated with improved lymphocyte recruitment and T cell-dependent tumor control. In patient PDAC tumors, rCAF resided next to TLS while myCAF were distally located. These data indicate that the myCAF-regulated PDAC stroma antagonizes acquisition of rCAF subsets critical for TLS formation but can be therapeutically remodeled to promote beneficial immune responses in immunosuppressive PDAC tumors.
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