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Proliferative exhausted CD8+ T cells exacerbate long-lasting anti-tumor effects in human papillomavirus-positive head and neck squamous cell carcinoma.

ABSTRACT: The survival prognosis of human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) is largely different, and little is known about the anti-tumor mechanism of tumor-infiltrated exhausted CD8+ T cells (Tex) in HNSCC. We performed cell-level multi-omics sequencing on human HNSCC samples to decipher the multi-dimensional characteristics of Tex cells. A proliferative exhausted CD8+ T cell cluster (P-Tex) which was beneficial to survival outcomes of patients with HPV-positive HNSCC was identified. Interestingly, P-Tex cells expressed CDK4 genes as high as cancer cells, which could be simultaneously inhibited by CDK4 inhibitors and might be a potential reason for the ineffectiveness of CDK4 inhibitors in treating HPV-positive HNSCC. P-Tex cells could aggregate in the antigen-presenting cell niches and activate certain signaling pathways. Together, our findings suggest a promising role for P-Tex cells in the prognosis of patients with HPV-positive HNSCC by providing modest but persistent anti-tumor effects.

SUBMITTER: Cheng D

PROVIDER: S-EPMC9946444 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Proliferative exhausted CD8+ T cells exacerbate long-lasting anti-tumor effects in human papillomavirus-positive head and neck squamous cell carcinoma.

Cheng Danni D Qiu Ke K Rao Yufang Y Mao Minzi M Li Li L Wang Yan Y Song Yao Y Chen Junren J Yi Xiaowei X Shao Xiuli X Huang Shao Hui SH Zhang Yi Y Chen Xuemei X Wu Sisi S Yu Shuaishuai S Liu Jun J Wang Haiyang H Peng Xingchen X Li Daibo D Yang Lin L Chen Li L Ying Zhiye Z Zheng Yongbo Y Zheng Meijun M Ying Binwu B Zeng Xiaoxi X Zhang Wei W Xu Wei W Liu Geoffrey G Chen Fei F Yu Haopeng H Zhao Yu Y Ren Jianjun J

eLife 20230222

The survival prognosis of human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) is largely different, and little is known about the anti-tumor mechanism of tumor-infiltrated exhausted CD8+ T cells (Tex) in HNSCC. We performed cell-level multi-omics sequencing on human HNSCC samples to decipher the multi-dimensional characteristics of Tex cells. A proliferative exhausted CD8+ T cell cluster (P-Tex) which was beneficial to survival ...[more]

PMID: 36811599

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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.

Project description:BackgroundThe 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.MethodsSix 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.ResultsWe 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.ConclusionsCD8+ 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.

Dataset Information

Proliferative exhausted CD8+ T cells exacerbate long-lasting anti-tumor effects in human papillomavirus-positive head and neck squamous cell carcinoma.

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Proliferative exhausted CD8<sup>+</sup> T cells exacerbate long-lasting anti-tumor effects in human papillomavirus-positive head and neck squamous cell carcinoma.

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