Dataset Information

CD8⁺ T-cell exhaustion in the tumor microenvironment of head and neck squamous cell carcinoma determines poor prognosis.

ABSTRACT:

Background

The occurrence of head and neck squamous cell carcinoma (HNSCC) is closely related to the immune system. The integration of traditional treatment methods and immunotherapy will be the future development direction of cancer treatment. But immunotherapy also has its limitations: a lot of basic research is going on, but the translation from basic to clinical is still not enough, and there are still few drugs approved for use.This study aimed to explore the clinical significance of the tumor immune microenvironment in HNSCC.

Methods

Six clinically obtained postoperative cases were analyzed using multiplex immunohistochemistry (mIHC) to observe the tumor immune microenvironment and analyze infiltrating immune cells. Correlations between infiltrating immune cells from The Cancer Genome Atlas (TCGA) database and clinicopathological features of 510 HNSCC patients were then analyzed. Kaplan-Meier survival analysis was used to detect the relationship between the expression of different immune cells and the prognosis of HNSCC patients, and univariate and multivariate Cox regression analyses were used to analyze the prognostic factors associated with HNSCC patients. We validated the prognostic and predictive accuracy based on the expression of CD8⁺ T-cells in an independent group of 510 patients.

Results

We detected infiltration of CD8⁺ T cells, NK cells, and macrophages in patients with laryngeal squamous cell carcinoma by multiplex immunofluorescence. The infiltration of the three types of immune cells in the tumor stroma was significantly higher than in the tumor parenchyma. Our results also showed the infiltration of CD8⁺ T cells was associated with prognosis, and the COX regression model showed CD8⁺ T cells were an independent prognostic factor in HNSCC patients. The higher density of infiltrating CD8⁺ T cells had the better prognosis. In addition, we developed a nomogram for clinical use that integrated the CD8⁺ T-cells-based classifier and three clinicopathological risk factors to predict the prognosis of HNSCC patients.

Conclusions

CD8⁺ T-cell exhaustion in the tumor microenvironment of HNSCC determines poor prognosis and can be combined with the tumor stage to improve the accuracy of prognosis assessment in HNSCC patients.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC9011205 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

CD8<sup>+</sup> T-cell exhaustion in the tumor microenvironment of head and neck squamous cell carcinoma determines poor prognosis.

Zhang Yijian Y Li Li L Zheng Wenjie W Zhang Lei L Yao Ninghua N

Annals of translational medicine 20220301 6

<h4>Background</h4>The occurrence of head and neck squamous cell carcinoma (HNSCC) is closely related to the immune system. The integration of traditional treatment methods and immunotherapy will be the future development direction of cancer treatment. But immunotherapy also has its limitations: a lot of basic research is going on, but the translation from basic to clinical is still not enough, and there are still few drugs approved for use.This study aimed to explore the clinical significance o ...[more]

PMID: 35434003

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Project description:Recent studies have identified SLC2A3 as being abnormally upregulated in multiple tumor types, correlating with poor survival and disrupted microenvironments. However, its prognostic significance in head and neck squamous cell carcinoma (HNSC) remains underexplored. In this study, SLC2A3 was screened as a potential risk gene influencing both immune and tumor components within the tumor microenvironment (TME) of 504 HNSC patients from the TCGA database. Immune infiltration analyses and clinical significance on SLC2A3 were conducted using ESTIMATE, CIBERSORT, ssGSEA, TIMER and clinical prognosis parameters. Additionally, the single-cell dataset is used to analyze the expression of SLC2A3 in various subpopulations. The magnetic activated cell sorting (MACS) is used to isolate CD8+ T cells from PBMCs or tumor tissues. Flow cytometry is used to identify purified and activated CD8+ T cells. GSEA and WB were used to investigate the molecular mechanism of SLC2A3 in CD8+ T cells. The co-culture system of CD8+ T cells and TU686 was used to investigate the effects of SLC2A3 on immune cells and tumor development. In this study, SLC2A3 was identified as a potential risk gene affecting both immune cells and tumor components within the TME of 504 HNSC patients derived from the TCGA database. We conducted immune infiltration analyses and assessed the clinical significance of SLC2A3 using various bioinformatics tools, including ESTIMATE, CIBERSORT, ssGSEA, and TIMER, along with clinical prognosis parameters. The single-cell RNA sequencing dataset was utilized to examine SLC2A3 expression across different cellular subpopulations. Magnetic activated cell sorting (MACS) was employed to isolate CD8+ T cells from peripheral blood mononuclear cells (PBMCs) or tumor tissues. Flow cytometry was implemented to confirm the purity and activation state of the isolated CD8+ T cells. GSEA and Western blot were applied to explore the molecular mechanisms underlying SLC2A3's role in CD8+ T cells. Lastly, a co-culture system involving CD8+ T cells and TU686 tumor cells was established to study the impact of SLC2A3 on immune cell function and tumor progression. SLC2A3 emerges as an actively variable gene within the immune and stromal components of the TME, linked to aggravated immune infiltration and poor clinical outcomes. The upregulated expression of SLC2A3 is predominantly enriched in immune-related biological processes and linked to the suppression of CD8+ T cells, which are crucial for the survival of HNSC patients. Furthermore, SLC2A3 exhibits specific overexpression in CD8+ T cells and may potentially trigger ferroptosis. Knockdown of SLC2A3 led to a significant increase in the proliferation of CD8+ T cells compared to those without knockdown. In co-culture systems, CD8+ T cells with SLC2A3 knockdown demonstrated an enhanced ability to eliminate tumor cells compared to those without the knockdown. SLC2A3 is associated with changes in the TME and prognostic indicators. Moreover, high SLC2A3 expression in CD8+ T cells may drive cell death through ferroptosis, fostering tumor progression.

Project description:BackgroundImmune cell heterogenicity is known to determine the therapeutic response to cancer progression. Neoadjuvant chemoimmunotherapy (NACI) has shown clinical benefits in some patients with advanced head and neck squamous cell carcinoma (HNSCC), but the underlying mechanism behind this clinical response is unknown. The efficacy of NACI needs to be potentiated by identifying accurate biomarkers to predict clinical responses. Here, we attempted to identify molecules predicting NACI response in advanced HNSCC.MethodsWe performed combined single-cell RNA sequencing (scRNA-seq) and multiplex immunofluorescence (mIHC) staining with tumor samples derived from NACI-treated HNSCC patients to identify a new tumor-infiltrating cell (TIL) subtype, CD103+ CD8+ TILs, associated with clinical response, while both in vitro and in vivo assays were carried out to determine its antitumor efficiency. The regulatory mechanism of the CD103+ CD8+ TILs population was examined by performing cell-cell interaction analysis of the scRNA-seq data and spatial analysis of the mIHC images.ResultsWe established intratumoral CD103+ CD8+ TILs density as a determinant of NACI efficacy in cancers. Our scRNA-seq results indicated that the population of CD103+ CD8+ TILs was dramatically increased in the responders of NACI-treated HNSCC patients, while mIHC analysis confirmed the correlation between intratumoral CD103+ CD8+ TILs density and NACI efficacy in HNSCC patients. Further receiver operating characteristic curve analysis defined this TIL subset as a potent marker to predict patient response to NACI. Functional assays showed that CD103+ CD8+ TILs were tumor-reactive T cells, while programmed cell death protein-1 (PD-1) blockade enhanced CD103+ CD8+ TILs cytotoxicity against tumor growth in vivo. Mechanistically, targeting the triggering receptor expressed on myeloid cells 2-positive (TREM2+ ) macrophages might enhance the population of CD103+ CD8+ TILs and facilitate antitumor immunity during NACI treatment.ConclusionsOur study highlights the impact of intratumoral CD103+ CD8+ TILs density on NACI efficacy in different cancers, while the efforts to elevate its population warrant further clinical investigation.

Dataset Information

CD8⁺ T-cell exhaustion in the tumor microenvironment of head and neck squamous cell carcinoma determines poor prognosis.

Background

Methods

Results

Conclusions

Publications

CD8<sup>+</sup> T-cell exhaustion in the tumor microenvironment of head and neck squamous cell carcinoma determines poor prognosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

CD8+ T-cell exhaustion in the tumor microenvironment of head and neck squamous cell carcinoma determines poor prognosis.

Background

Methods

Results

Conclusions

Publications

CD8<sup>+</sup> T-cell exhaustion in the tumor microenvironment of head and neck squamous cell carcinoma determines poor prognosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

CD8⁺ T-cell exhaustion in the tumor microenvironment of head and neck squamous cell carcinoma determines poor prognosis.