Checkpoint blockade induced CD8+ T cell differentiation in responders in head and neck cancers
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA642178 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12099910.fastq.gz | Fastqsanger.gz | |||
| SRR12099911.fastq.gz | Fastqsanger.gz | |||
| SRR12099912.fastq.gz | Fastqsanger.gz | |||
| SRR12099913.fastq.gz | Fastqsanger.gz | |||
| SRR12099914.fastq.gz | Fastqsanger.gz |
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Project description:Background: Outcomes for locally advanced or recurrent/ metastatic head and neck squamous cell carcinomas (HNSCCs) remain unfavorable despite recent advances with immune checkpoint blockade (ICB). Preclinical studies using model antigens identified a critical role of CD8+TCF7+PD1+ T cells in anti-PD1 response. Studies on the heterogeneity and clonal dynamics of global tumor infiltrating T lymphocytes (TILs) in the HNSCC anti-PD1 and anti-CTLA4 response have not been explored. Results: In this study, we generated isogenic HNSCC anti-PD1 sensitive/resistant models that bore distinct cancer cell intrinsic transcriptomic programs. Tumor microenvironment characterization using mass cytometry and targeted depletion revealed the contribution of Tregs and M2-like macrophages in anti-PD1 resistance. Paired single-cell RNA and TCR sequencing on tumor infiltrating immune cells from ICB responsive and resistant HNSCC models identified a spectrum of CD8+ TIL subsets including TCF7+PD1- (naïve/memory-like), TCF7+PD1+ (progenitor exhausted), and TCF7-PD1+ (terminally exhausted). Mapping TCR shared fractions between these subsets identified that successful anti-PD1 or anti-CTLA4 therapy induced higher post-treatment T cell lineage transitions. A TIL differentiation gene signature was associated with better responses in multiple ICB clinical trials. Conclusions: Together, analyses integrating scRNAseq and TCRseq demonstrate distinct differentiation dynamics of CD8+ TILs in novel ICB responsive and resistant HNSCC models, highlighting critical aspects of CD8+ TIL differentiation in response to ICB.
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Project description:To investigate the effects of Piezo-CAP on various types of HNC cells and elucidate the underlying mechanisms. Additionally, we examined the efficacy of combining Piezo-CAP with chemotherapy drugs (cisplatin) or immune checkpoint blockade (ICB) in head and neck tumor treatment. RNA-sequence (RNA-seq), Western blot and quantitative real-time PCR (qRT-PCR) were utilized to investigate the mechanism of Piezo-CAP treatment HNC cells.
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Project description:Immune checkpoint blockade (ICB) response in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is limited to 15%-20% of patients and underpinnings of resistance remain undefined. Starting with an anti-PD1 sensitive murine HNSCC cell line, we generated an isogenic anti-PD1 resistant model. Mass cytometry was used to delineate tumor microenvironments of both sensitive parental murine oral carcinoma (MOC1) and resistant MOC1esc1 tumors. To examine heterogeneity and clonal dynamics of tumor infiltrating lymphocytes (TILs), we applied paired single-cell RNA and TCR sequencing in three HNSCC models. Anti-PD1 resistant MOC1esc1 line displayed a conserved cell intrinsic immune evasion signature. Immunoprofiling showed distinct baseline tumor microenvironments of MOC1 and MOC1esc1, as well as the remodeling of immune compartments on ICB in MOC1esc1 tumors. Single cell sequencing analysis identified several CD8 +TIL subsets including Tcf7 +Pd1- (naïve/memory-like), Tcf7 +Pd1+ (progenitor), and Tcf7-Pd1+ (differentiated effector). Mapping TCR shared fractions identified that successful anti-PD1 or anti-CTLA4 therapy-induced higher post-treatment T cell lineage transitions. These data highlight critical aspects of CD8 +TIL heterogeneity and differentiation and suggest facilitation of CD8 +TIL differentiation as a strategy to improve HNSCC ICB response.
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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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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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Project description:Transcriptional profiling was performed on biopsies from patients with head and neck squamous cell carcinoma that had been treated with cisplatin and 5-fluorouracil to identify genes predictive of response to chemotherapy Two condition experiment, Biopsies from complete clinical responders and from non-responders were compared based upon a common reference using a two color design
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Project description:Immune checkpoint blockade (ICB) therapy has demonstrated promising clinical results in oncology and is currently one of the most sought-after immunotherapies for tumors. However, there are a number of issues with ICB therapy, including low response rates and a lack of effective efficacy predictors. Gasdermin-mediated pyroptosis is a typical form of inflammatory death mode, but it is unclear whether ICB treatment can trigger its occurrence or whether gasdermin expression has any effect on the response rate to ICB treatment. Herein, we discovered that high expression of gasdermin protein was associated with a favorable tumor immune microenvironment and a favorable prognosis in head and neck squamous cell carcinoma (HNSCC), and taking advantage of the mouse HNSCC cell line 4MOSC1 (responsive to CTLA-4 blockade) and 4MOSC2 (resistant to CTLA-4 blockade) orthotopic models, we also demonstrated that CTLA-4 blockade treatment induced gasdermin-mediated pyroptosis of tumor cells and that the expression of gasdermin was positively associated with the effectiveness of CTLA-4 blocking treatment. Mechanistically, through RNA sequencing, flow cytometry, ELISA, Western blotting and RT-PCR, we discovered that CTLA-4 blockade activated CD8+ T cells in the tumor and increased the levels of the cytokines TNF-α and IFN-γ in the tumor microenvironment, and that TNF-α and IFN-γ synergistically activated the STAT1/IRF1 axis, inducing tumor cell pyroptosis and the release of large amounts of inflammatory substances and chemokines such as CXCL10.
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Project description:Coinhibitory receptor blockade is a promising strategy to boost immunity against a variety of human cancers. However, many patients still do not benefit from this treatment, and responders often experience immune-related toxicities. These issues highlight the need for improved understanding of checkpoint blockade, but the T cell-intrinsic signaling pathways and gene expression profiles engaged during treatment are not well defined, particularly for combination approaches. We utilized a murine model of CD8+ T cell tolerance to address these issues. We used microarrays to examine the global transcriptional response of T cells rendered tolerant in vivo by encounter with tumor/self-antigen versus T cells activated in response to an immunogenic tumor. RNA isolated from naive Gag-specific T cells was compared to RNA isolated from T-cells transferred into B6 mice with established FBL tumor (immune) and from Alb:Gag mice (tolerant). Two days after T cell transfer, recipient spleen and lymph nodes were harvested and pooled. Transferred cells were then sorted based on CD8+ CD90.1+ CD69hi to a >96% purity using a FACSAria III (BD Biosciences). There were 3 biological replicates per condition.
2014-12-18 | E-GEOD-58722 | biostudies-arrayexpress