Resident memory T cells in tumor-distant tissues fortify against metastasis formation

Christian, Laura S.; Wang, Liuyang; Lim, Bryan Jian Wei; Deng, Dachuan; Wu, Haiyang; Wang, Xiaofan; Li, Qi-Jing

doi:10.1016/j.celrep.2021.109118

Cited by 23 publications

(18 citation statements)

References 98 publications

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“…An ambivalent role of CXCR6 + T cells in tumor control has been reported. Thus, in many models, CXCR6 + CD8 + T cells of resident phenotype participate in the control of primary tumor proliferation and metastasis ( 12 , 57 , 62 ). On the contrary, in NASH models with significant chronic inflammation, CXCR6 + P2X7 + T cells are able to destroy hepatocytes in a non-MHC-restricted manner which distinguishes them from classical CD8 + T RM ( 11 , 73 ).…”

Section: Discussionmentioning

confidence: 99%

“…Cxcr6 - deficient mice or CXCL16 neutralizing Ab resulted in an enhanced metastasis to the liver by B16 melanoma cells or Lewis Lung tumor cells ( 61 ). In another preclinical model of lung metastases from breast cancer, it has been shown that CXCR6 - T effectors are the major subset preferentially egressing the tumor to form distant CXCR6 + T RM , whereas intratumoral CXCR6 + T cells are retained in the tumor ( 62 ). Breaking CXCR6-mediated retention in the tumor by anti-CXCL16 treatment resulted in more T cells egressing to the distant lung tissue and a decrease metastatic tumor burden ( 62 ).…”

Section: Role Of Cxcr6 + T Cells In Cancermentioning

confidence: 99%

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CXCR6 expressing T cells: Functions and role in the control of tumors

et al. 2022

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CXCR6 is a receptor for the chemokine CXCL16, which exists as a membrane or soluble form. CXCR6 is a marker for resident memory T (TRM) cells that plays a role in immunosurveillance through their interaction with epithelial cells. The interaction of CXCR6 with CXCL16 expressed at the membrane of certain subpopulations of intratumor dendritic cells (DC) called DC3, ideally positions these CXCR6+ T cells to receive a proliferation signal from IL-15 also presented by DC3. Mice deficient in cxcr6 or blocking the interaction of CXCR6 with its ligand, experience a poorer control of tumor proliferation by CD8+ T cells, but also by NKT cells especially in the liver. Intranasal vaccination induces CXCL16 production in the lungs and is associated with infiltration by TRM expressing CXCR6, which are then required for the efficacy of anti-tumor vaccination. Therapeutically, the addition of CXCR6 to specific CAR-T cells enhances their intratumoral accumulation and prolongs survival in animal models of pancreatic, ovarian and lung cancer. Finally, CXCR6 is part of immunological signatures that predict response to immunotherapy based on anti-PD-(L)1 in various cancers. In contrast, a protumoral role of CXCR6+T cells has also been reported mainly in Non-alcoholic steatohepatitis (NASH) due to a non-antigen specific mechanism. The targeting and amplification of antigen-specific TRM expressing CXCR6 and its potential use as a biomarker of response to immunotherapy opens new perspectives in cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Role Of Cxcr6 + T Cells In Cancermentioning

confidence: 99%

CXCR6 expressing T cells: Functions and role in the control of tumors

et al. 2022

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“…Functionally, CXCR6 + Trm cells are required to sustain the proliferation and antitumor effects of cytotoxic T lymphocytes [42,50]. CXCR6 + Trms control tumor growth and metastasis [42,50,51] and are equipped with immunosurveillance to restrain tumor recurrence [52,53]. A recent study demonstrated that Klf5 loss led to a reduced number of myeloid-derived cells, particularly granulocytic myeloid-derived suppressor cells (gMDSCs), but an augmented number of both CD4 + and CD8 + T cells in pancreatic cancer models [26].…”

Section: Discussionmentioning

confidence: 99%

KLF5 inhibition potentiates anti-PD1 efficacy by enhancing CD8⁺ T-cell-dependent antitumor immunity

Wu¹,

Liu²,

Gao³

et al. 2023

Theranostics

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Background: Immune checkpoint blockers (ICBs) are revolutionized therapeutic strategies for cancer, but most patients with solid neoplasms remain resistant to ICBs, partly because of the difficulty in reversing the highly immunosuppressive tumor microenvironment (TME). Exploring the strategies for tumor immunotherapy is highly dependent on the discovery of molecular mechanisms of tumor immune escape and potential therapeutic target. Krüppel-like Factor 5 (KLF5) is a cell-intrinsic oncogene to promote tumorigenesis. However, the cell-extrinsic effects of KLF5 on suppressing the immune response to cancer remain unclear. Methods:We analyzed the immunosuppressive role of KLF5 in mice models transplanted with KLF5-deleted/overexpressing tumor cells. We performed RNA sequencing, immunohistochemistry, western blotting, real time-PCR, ELISA, luciferase assay, chromatin immunoprecipitation (ChIP), and flow cytometry to demonstrate the effects of KLF5 on CD8 + T cell infiltration and related molecular mechanism. Single-cell RNA sequencing and spatial transcriptomics analysis were applied to further decipher the association between KLF5 expression and infiltrating immune cells. The efficacy of KLF5/COX2 inhibitors combined with anti-programmed cell death protein 1 (anti-PD1) therapy were explored in pre-clinical models. Finally, a gene-expression signature depending on KLF5/COX2 axis and associated immune markers was created to predict patient survival.KLF5 is associated with an immune-supportive TME. Finally, we generate a KLF5/COX2-associated immune score (KC-IS) to predict patient survival. Conclusions:Our results identified a novel mechanism responsible for KLF5-mediated immunosuppression in TME, and targeting the KLF5/COX2/PGE2 axis is a critical immunotherapy sensitizer.

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“…T-CELL. The T-CELL dataset was generated in our previous study [24]. The benchmark clustering labels of the T-CELL population were generated as a combination of protein-marker-based flow sorting labels and bioinformatics labels from Seurat v2.…”

Section: Experimental Datasetsmentioning

confidence: 99%

Clustering Deviation Index (CDI): a robust and accurate internal measure for evaluating scRNA-seq data clustering

et al. 2022

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Most single-cell RNA sequencing (scRNA-seq) analyses begin with cell clustering; thus, the clustering accuracy considerably impacts the validity of downstream analyses. In contrast with the abundance of clustering methods, the tools to assess the clustering accuracy are limited. We propose a new Clustering Deviation Index (CDI) that measures the deviation of any clustering label set from the observed single-cell data. We conduct in silico and experimental scRNA-seq studies to show that CDI can select the optimal clustering label set. As a result, CDI also informs the optimal tuning parameters for any given clustering method and the correct number of cluster components.

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Resident memory T cells in tumor-distant tissues fortify against metastasis formation

Cited by 23 publications

References 98 publications

CXCR6 expressing T cells: Functions and role in the control of tumors

CXCR6 expressing T cells: Functions and role in the control of tumors

KLF5 inhibition potentiates anti-PD1 efficacy by enhancing CD8⁺ T-cell-dependent antitumor immunity

Clustering Deviation Index (CDI): a robust and accurate internal measure for evaluating scRNA-seq data clustering

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Resident memory T cells in tumor-distant tissues fortify against metastasis formation

Cited by 23 publications

References 98 publications

CXCR6 expressing T cells: Functions and role in the control of tumors

CXCR6 expressing T cells: Functions and role in the control of tumors

KLF5 inhibition potentiates anti-PD1 efficacy by enhancing CD8+ T-cell-dependent antitumor immunity

Clustering Deviation Index (CDI): a robust and accurate internal measure for evaluating scRNA-seq data clustering

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KLF5 inhibition potentiates anti-PD1 efficacy by enhancing CD8⁺ T-cell-dependent antitumor immunity