Investigating Immune and Non-Immune Cell Interactions in Head and Neck Tumors by Single-Cell RNA Sequencing
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE164690 | GEO | 2021/11/08
REPOSITORIES: GEO
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Project description:Head and neck squamous cell carcinoma (HNSCC) arises through exposure to environmental carcinogens or malignant transformation by human papillomavirus (HPV). Here, we assessed the transcriptional profiles of 131,224 single cells from peripheral and intra-tumoral CD45+ immune populations from HPV– and HPV+ HNSCC and healthy donors. A spectrum of transcriptional signatures in immune lineages ranging from similar to highly divergent was present in the tumor microenvironments (TME) in HPV– and HPV+ HNSCC. CD8+ and regulatory CD4+ T cells were similar in HPV– and HPV+ HNSCC, compared to significant differences between helper CD4+ T cells, B cells and myeloid cells. Further dissection of the major immune lineages identified unique cell states and differentiation trajectories. We contextualized our results by performing multispectral immunofluorescence and evaluating putative cell-cell communication based on spatial proximity, and found longer progression free survival in patients with enrichment of a CD4+ T follicular helper cell signature.
2019-11-13 | GSE139324 | GEO
Project description:We previously identified stress keratin 17 (K17) as a host factor that contributes to immune evasion in the context of mouse papillomavirus-induced disease. Analyses of head and neck squamous cell carcinoma (HNSCC) patient TCGA and tissue microarray data revealed that K17 can be overexpressed in both HPV+ and HPV- human cancer samples, with a more profound upregulation in HPV- HNSCC samples. In this report, we investigated the role of K17 in regulating immune response in HPV- head and neck cancer. To test whether K17 mediates immune evasion and resistance to immune checkpoint blockade (ICB) therapy in HPV- HNC, we used MOC2, a K17-expressing murine HNC cell line, and knocked out the K17 gene from it using CRISPR/Cas9 (K17KO MOC2 cells). Then we injected K17KO MOC2 cells or parental MOC2 cells into NSG and C57BL/6 mice and monitored tumor growth, immune cell infiltration, and response to ICB treatment in vivo. In NSG mice, the K17KO MOC2 cell lines grew as fast as parental MOC2 tumors. In C57BL/6 mice, K17KO MOC2 tumors grew significantly slower than parental MOC2 tumors, with 50% tumor rejection rate, in a T-cell dependent manner. Flow cytometry of tumor infiltrating T cells and bulk tumor RNA seq analyses show an active anti-tumor microenvironment in the K17KO MOC2 tumors, compared to parental MOC2 tumors. In addition, we observed that 5 out of 5 anti-PD1 + anti-CTLA4 treated K17KO MOC2 tumors completely regressed, while only 1 out of 5 parental MOC2 tumors similarly treated at the same size completely regressed (p<0.05). In exploring the role of chemokine CXCL9 in increased T cell infiltration, we blocked the receptor CXCR3, a receptor often upregulated on activated T cells, and saw a delay in the immune-mediated rejection K17KO MOC2 tumors. Single cell RNA seq analyses revealed a completely different immune landscape including both lymphoid and myeloid populations in K17KO MOC2 tumors. Overall, we demonstrated that K17 expression in HNSCC contributes to immune evasion and resistance to immune checkpoint blockade treatment through modulating the immune landscape in the tumor microenvironment.
2022-07-06 | GSE182026 | GEO
Project description:We previously identified stress keratin 17 (K17) as a host factor that contributes to immune evasion in the context of mouse papillomavirus-induced disease. Analyses of head and neck squamous cell carcinoma (HNSCC) patient TCGA and tissue microarray data revealed that K17 can be overexpressed in both HPV+ and HPV- human cancer samples, with a more profound upregulation in HPV- HNSCC samples. In this report, we investigated the role of K17 in regulating immune response in HPV- head and neck cancer. To test whether K17 mediates immune evasion and resistance to immune checkpoint blockade (ICB) therapy in HPV- HNC, we used MOC2, a K17-expressing murine HNC cell line, and knocked out the K17 gene from it using CRISPR/Cas9 (K17KO MOC2 cells). Then we injected K17KO MOC2 cells or parental MOC2 cells into NSG and C57BL/6 mice and monitored tumor growth, immune cell infiltration, and response to ICB treatment in vivo. In NSG mice, the K17KO MOC2 cell lines grew as fast as parental MOC2 tumors. In C57BL/6 mice, K17KO MOC2 tumors grew significantly slower than parental MOC2 tumors, with 50% tumor rejection rate, in a T-cell dependent manner. Flow cytometry of tumor infiltrating T cells and bulk tumor RNA seq analyses show an active anti-tumor microenvironment in the K17KO MOC2 tumors, compared to parental MOC2 tumors. In addition, we observed that 5 out of 5 anti-PD1 + anti-CTLA4 treated K17KO MOC2 tumors completely regressed, while only 1 out of 5 parental MOC2 tumors similarly treated at the same size completely regressed (p<0.05). In exploring the role of chemokine CXCL9 in increased T cell infiltration, we blocked the receptor CXCR3, a receptor often upregulated on activated T cells, and saw a delay in the immune-mediated rejection K17KO MOC2 tumors. Single cell RNA seq analyses revealed a completely different immune landscape including both lymphoid and myeloid populations in K17KO MOC2 tumors. Overall, we demonstrated that K17 expression in HNSCC contributes to immune evasion and resistance to immune checkpoint blockade treatment through modulating the immune landscape in the tumor microenvironment.
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Project description:Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and the human papillomavirus (HPVP+P)-driven subtype is the fastest rising in North America. Although most cases of HPV+ HNSCC respond to radiation and chemotherapy in combination with surgery, up to 20% of patients recur after primary treatment with poor prognosis. To gain insights into the mechanism of recurrence to inform patient stratification and precision treatment, we carried out RNA-seq analysis on 43 HPV+ HNSCC specimens, of which 15, including 7 recurrent tumors, were analyzed by quantitative mass spectrometry. The proteome and phosphoproteome, but not the transcriptome, were found to be distinct between the recurrent and non-recurrent tumors. Specifically, recurrent tumors featured a pro-fibrotic and immune suppressive tumor microenvironment (TME) characterized with more abundant cancer associated fibroblasts, extracellular matrix (ECM), neutrophils and suppressive myeloid cells, increased potential for epithelial-mesenchymal transition and defective T cell function, accompanied by aberrant changes in the corresponding signaling pathways. Mechanistically, kinome reprogramming played a pivotal role in mediating recurrence through regulating TME remodelling, cytoskeletal reorganization, cell adhesion, neutrophil function, and coagulation. Besides providing systems-level insights into the molecular basis of recurrence, our work led to the identification of numerous mechanism-based biomarkers and therapeutic targets that may aid future endeavours of developing prognostic biomarkers and precision medicine for recurrent HPV+ HNSCC.
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Project description:<p>Plasmacytoid dendritic cells (pDC) are a subset of dendritic cells with unique immunophenotypic properties and functions. While their role in antiviral immunity through production of type I interferons is well-established, their contributions to anti-tumor immunity are less clear. While some evidence demonstrates that pDC in the tumor microenvironment (TME) may drive CD4+ T cell to become <a href="https://www.ncbi.nlm.nih.gov/gene/50943">Foxp3</a>+ T regulatory cells, little is understood about the relationship of pDC with cytotoxic CD8+ T cell, the key player in antitumor immune responses.</p> <p>In this study, we perform comprehensive immunophenotyping and functional analysis of pDC from the TME and draining lymph nodes of patients with head and neck squamous cell carcinoma (HNSCC) and identify a novel pDC subset characterized by expression of the TNF receptor superfamily member <a href="https://www.ncbi.nlm.nih.gov/gene/?term=7293">CD134 (OX40)</a>. We show that OX40 expression is expressed on intratumoral pDC in both humans and mice in a tumor-model specific fashion and that this subset of pDC enhances tumor associated-antigen (TAA)-specific CD8+ T cell responses. Through transcriptomic profiling of OX40-expressing pDC from the TME, we further characterize gene signatures unique to this pDC subset that support its role as an important immunostimulatory immune population in the TME.</p>
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Project description:Tumor microenvironment (TME) plays an important role in immune evasion and resistance to immune checkpoint therapy. Here, by using genetic, epigenetic, tumor biology and immunology approaches, we unraveled a key function of KDM1B in TME. KDM1B is important for maintaining several pro-oncogenic cytokine/chemokine signaling pathways. In vivo in resistant and inflammatory breast cancer models, ablation of KDM1B in tumor cells results in increased T cell activity and significantly improved response to anti-PD-1/anti-CTLA-4 therapy. Thus, this study identifies KDM1B as a key regulator of tumor immune microenvironment and offered the mechanistical basis for using KDM1B inhibitors in combinatory therapy to overcome resistance to immune checkpoint blockade.
2021-06-01 | GSE135344 | GEO
Project description:Tumor microenvironment (TME) plays an important role in immune evasion and resistance to immune checkpoint therapy. Here, by using genetic, epigenetic, tumor biology and immunology approaches, we unraveled a key function of KDM1B in TME. KDM1B is important for maintaining several pro-oncogenic cytokine/chemokine signaling pathways. In vivo in resistant and inflammatory breast cancer models, ablation of KDM1B in tumor cells results in increased T cell activity and significantly improved response to anti-PD-1/anti-CTLA-4 therapy. Thus, this study identifies KDM1B as a key regulator of tumor immune microenvironment and offered the mechanistical basis for using KDM1B inhibitors in combinatory therapy to overcome resistance to immune checkpoint blockade.
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2024-01-01 | E-MTAB-12922 | biostudies-arrayexpress
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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