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In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion [in vivo]

ABSTRACT: Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a high unmet need for enhancing immunotherapy given current modest responses. Here, we performed an in vivo CRISPR screen in a HNSCC mouse model to identify immune evasion genes. We identified several epigenetic regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of Uchl5 in tumors increased CD8+ T cell infiltration and improved ICB responses. Uchl5 deficiency reduced extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional signatures, which contribute to stromal desmoplasia, a histologic finding associated with reduced anti-PD1 response in human HNSCCs. We identified a functional role for COL17A1, a collagen highly and specifically expressed in HNSCC, in Uchl5-mediated immune evasion. Our findings suggest an unappreciated role for UCHL5 in promoting EMT in HNSCC and highlight ECM modulation as a strategy to improve immunotherapy responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE269445 | GEO | 2025/06/07

REPOSITORIES: GEO

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In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion.

Project description:Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a high unmet need for enhancing immunotherapy given current modest responses. Here, we performed an in vivo CRISPR screen in a HNSCC mouse model to identify immune evasion genes. We identified several epigenetic regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of Uchl5 in tumors increased CD8+ T cell infiltration and improved ICB responses. Uchl5 deficiency reduced extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional signatures, which contribute to stromal desmoplasia, a histologic finding associated with reduced anti-PD1 response in human HNSCCs. We identified a functional role for COL17A1, a collagen highly and specifically expressed in HNSCC, in Uchl5-mediated immune evasion. Our findings suggest an unappreciated role for UCHL5 in promoting EMT in HNSCC and highlight ECM modulation as a strategy to improve immunotherapy responses.

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In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion [in vitro]

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UCHL5 promotes Tumorigenesis of Bladder Cancer by Activating AKT/mTOR signaling pathway and targeting c-myc, SLC25A19, and ICAM5.

Project description:Purpose: To investigate the tumor-promoting role of UCHL5 in bladder cancer. Method: We established the UCHL5 knockdown cell line in which the target gene was knocked down by shRNA. RNA was extracted from cells using trizol reagent(Invitrogen) Result: Through RNA-sequencing analysis of wild-type and UCHL5 deficient T24 cell lines, the downstream signaling pathways that UCHL5 may be involved in were determined. We found that the AKT/mTOR signaling pathway and c-Myc,SLC25A19, and ICAM5 were significantly inactivated when UCHL5 was knocked down in bladder cancer. Conclusion: UCHL5 enhances the AKT/mTOR pathway, which consequently upgraded the expression of c-myc,SLC25A19, and ICAM5, ultimately promoting the occurrence and progression of bladder cancer. UCHL5 may suggest potential utility for bladder cancer therapy.

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Immune checkpoint inhibitor monotherapy is sufficient to promote microenvironmental normalization via Type I interferon pathway in PD-L1+ expressing head and neck cancer

Project description:Immune checkpoint blockers (ICBs) targeting programmed death 1(PD-1) are considered effective first-line therapy against PD-1 ligand (PD-L1)-expressing head and neck squamous cell carcinoma (HNSCC). However, associated changes in tumor microenvironment (TME) and mechanisms remain elusive. Oral tumors in C57/BL6 mice were induced by administering 7,12-dimethylbenzanthracene into the buccal mucosa. Single-cell suspension was isolated from tumor tissue; proliferating cells were injected subcutaneously into the left flank of mice to establish Ajou Oral Cancer (AOC) cell lines. Subsequently, a syngeneic PD-L1-expressing HNSCC xenograft model was developed by injecting AOC cells into the buccal or tongue area. The model recapitulated human HNSCC molecular features and showed reliable in vivo tumorigenicity with significant PD-L1 expression. ICB monotherapy induced global changes in TME, including vascular normalization. Furthermore, the anti-tumor effect of ICB monotherapy was superior to those of other therapeutic agents, including cisplatin and anti-vascular endothelial growth factor receptor 2 inhibitors. The ICB-induced anti-tumorigenicity and TME normalization were alleviated by blocking the Type I interferon pathway.In summary, ICB monotherapy is sufficient to induce TME normalization in the syngeneic model; the Type-I interferon pathway is indispensable in realizing ICB effects. Furthermore, these results explain the underlying mechanism of the efficacy of ICB monotherapy against HNSCC expressing PD-L1 in the KEYNOTE-048 trial. This model can assist future research on HNSCC immunotherapy.

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Project description:Immune checkpoint blockade (ICB) has improved outcomes in head and neck squamous cell carcinoma (HNSCC), yet there is an unmet need for predictive, blood-based biomarkers to guide treatment. We longitudinally profiled peripheral immune responses in a mouse HNSCC model treated with anti–PD-1, using single-cell and bulk RNA sequencing with paired TCR sequencing. Early expansion of effector memory T cells (Tem) and B cells was associated with ICB response. Here, we show that the LiBIO score, a composite of Tem and B cell signatures, robustly predicts ICB response in HNSCC blood and tumor cohorts, outperforming existing biomarkers. Furthermore, the LiBIO score generalizes to melanoma, non-small cell lung cancer, and breast cancer, demonstrating potential as a clinically applicable blood-based biomarker for ICB response across multiple cancer types.

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In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion [in vivo]

Project description:In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion [in vivo]

| PRJNA1121933 | ENA

In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion.

Project description:In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion.

| PRJNA1211115 | ENA

In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion

Project description:In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion

| PRJNA1121930 | ENA

PABPC1L promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in renal cell carcinoma

Project description:The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance though highly infiltrated by T cells. There is an urgent need to elucidate tumor immune evasion and to develop novel therapeutic target to boost the efficacy of immune checkpoint blockade (ICB) in RCC. Our study uncovers a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine2, 3dioxygenase1 (IDO1), a prospective candidate for immunotherapy. PABPC1L, markedly upregulated in RCC, correlates with unfavorable prognosis and resistance to ICB. Overexpressed PABPC1L bolsters tryptophan metabolism and induces T-cell dysfunction by stabilizing IDO1. Conversely, silencing PABPC1L diminishes IDO1 expression, mitigates cytotoxic T-cell suppression, and enhances responsiveness to anti-PD-1 therapy. Our findings underscore PABPC1L's crucial role in facilitating immune evasion in RCC, making it a potential addition to ICB therapy.

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