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CXCR6 deficiency impairs cancer vaccine efficacy and CD8⁺ resident memory T-cell recruitment in head and neck and lung tumors.

ABSTRACT:

Background

Resident memory T lymphocytes (T_RM) are located in tissues and play an important role in immunosurveillance against tumors. The presence of T_RM prior to treatment or their induction is associated to the response to anti-Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) immunotherapy and the efficacy of cancer vaccines. Previous work by our group and others has shown that the intranasal route of vaccination allows more efficient induction of these cells in head and neck and lung mucosa, resulting in better tumor protection. The mechanisms of in vivo migration of these cells remains largely unknown, apart from the fact that they express the chemokine receptor CXCR6.

Methods

We used CXCR6-deficient mice and an intranasal tumor vaccination model targeting the Human Papillomavirus (HPV) E7 protein expressed by the TC-1 lung cancer epithelial cell line. The role of CXCR6 and its ligand, CXCL16, was analyzed using multiparametric cytometric techniques and Luminex assays.Human biopsies obtained from patients with lung cancer were also included in this study.

Results

We showed that CXCR6 was preferentially expressed by CD8⁺ T_RM after vaccination in mice and also on intratumoral CD8⁺ T_RM derived from human lung cancer. We also demonstrate that vaccination of Cxcr6-deficient mice induces a defect in the lung recruitment of antigen-specific CD8⁺ T cells, preferentially in the T_RM subsets. In addition, we found that intranasal vaccination with a cancer vaccine is less effective in these Cxcr6-deficient mice compared with wild-type mice, and this loss of efficacy is associated with decreased recruitment of local antitumor CD8⁺ T_RM. Interestingly, intranasal, but not intramuscular vaccination induced higher and more sustained concentrations of CXCL16, compared with other chemokines, in the bronchoalveolar lavage fluid and pulmonary parenchyma.

Conclusions

This work demonstrates the in vivo role of CXCR6-CXCL16 axis in the migration of CD8⁺ resident memory T cells in lung mucosa after vaccination, resulting in the control of tumor growth. This work reinforces and explains why the intranasal route of vaccination is the most appropriate strategy for inducing these cells in the head and neck and pulmonary mucosa, which remains a major objective to overcome resistance to anti-PD-1/PD-L1, especially in cold tumors.

SUBMITTER: Karaki S

PROVIDER: S-EPMC7949477 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer1,2. Here we studied CD8 T cells in patients with human papillomavirus (HPV)-positive head and neck cancer and identified several epitopes derived from HPV E2, E5 and E6 proteins that allowed us to analyse virus-specific CD8 T cells using major histocompatibility complex (MHC) class I tetramers. HPV-specific CD8 T cells expressed PD-1 and were detectable in the tumour at levels that ranged from 0.1% to 10% of tumour-infiltrating CD8 T lymphocytes (TILs) for a given epitope. Single-cell RNA-sequencing analyses of tetramer-sorted HPV-specific PD-1+ CD8 TILs revealed three transcriptionally distinct subsets. One subset expressed TCF7 and other genes associated with PD-1+ stem-like CD8 T cells that are critical for maintaining T cell responses in conditions of antigen persistence. The second subset expressed more effector molecules, representing a transitory cell population, and the third subset was characterized by a terminally differentiated gene signature. T cell receptor clonotypes were shared between the three subsets and pseudotime analysis suggested a hypothetical differentiation trajectory from stem-like to transitory to terminally differentiated cells. More notably, HPV-specific PD-1+TCF-1+ stem-like TILs proliferated and differentiated into more effector-like cells after in vitro stimulation with the cognate HPV peptide, whereas the more terminally differentiated cells did not proliferate. The presence of functional HPV-specific PD-1+TCF-1+CD45RO+ stem-like CD8 T cells with proliferative capacity shows that the cellular machinery to respond to PD-1 blockade exists in HPV-positive head and neck cancer, supporting the further investigation of PD-1 targeted therapies in this malignancy. Furthermore, HPV therapeutic vaccination efforts have focused on E6 and E7 proteins; our results suggest that E2 and E5 should also be considered for inclusion as vaccine antigens to elicit tumour-reactive CD8 T cell responses of maximal breadth.

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.

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CXCR6 deficiency impairs cancer vaccine efficacy and CD8⁺ resident memory T-cell recruitment in head and neck and lung tumors.

Background

Methods

Results

Conclusions

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

CXCR6 deficiency impairs cancer vaccine efficacy and CD8+ resident memory T-cell recruitment in head and neck and lung tumors.

Background

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

CXCR6 deficiency impairs cancer vaccine efficacy and CD8⁺ resident memory T-cell recruitment in head and neck and lung tumors.