Immunotherapy resistance in melanoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB45846 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR6097350.fastq.gz | Fastqsanger.gz | |||
| ERR6097360.fastq.gz | Fastqsanger.gz | |||
| ERR6097370.fastq.gz | Fastqsanger.gz | |||
| ERR6097380.fastq.gz | Fastqsanger.gz | |||
| ERR6097351.fastq.gz | Fastqsanger.gz |
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Project description:Programmed death-ligand 1, PD-L1 (CD274) facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a new mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic-hedgehog (Shh) and TGF- receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBC), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein Caprin-1 to stabilize Shh/TGFBR1/Wnt mRNAs to induce -catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ T regs and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using Sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.
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Project description:<p>The effectiveness of immunotherapy varies among patients with advanced non-small cell lung cancer (NSCLC). Here we investigated the baseline immune status in stage IV NSCLC patients treated with anti-PD-1 plus chemotherapy to understand the immune mechanisms and unveil systemic markers associated with treatment response. Responders had elevated frequencies of circulating T cells expressing CD69, TCF-1 and CXCR-3. In contrast, non-responders presented increased frequencies of CTLA-4, CD161 and IL-10 expressing CD4+ and CD8+ T cells. These systemic T cell immune profiles were mirrored in the tumor microenvironment of an independent cohort. Concurrent CTLA-4 and PD-1 blockade was able to reactivate an anti-tumor profile in T cells from non-responder patients, emphasizing the pivotal role of CTLA-4 in contributing to an immunosuppressive environment that hinders effective treatment in NSCLC. This work supports the implementation of personalized immunotherapies based on systemic immune biomarkers, offering a promising approach to enhance treatment outcomes in advanced NSCLC.</p>
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