Cancer cell-expressed BTNL2 facilitates tumour immune escape via engagement with IL-17A-producing γδ T cells

Du, Yanyun; Peng, Qianwen; Cheng, Du; Pan, Ting; Sun, Wanwei; Wang, Heping; Ma, Xiaojian; He, Ruirui; Zhang, Huazhi; Cui, Zhenzhong; Xiong, Feng; Liu, Zhiqiang; Zhao, Tianxin; Hu, Wenjun; Shen, Lei; Jiang, Wenyang; Gao, Na; Martin, Bradley N.; Zhang, Cun-Jin; Zhang, Zhanguo; Wang, Chenhui

doi:10.1038/s41467-021-27936-8

Cited by 24 publications

(30 citation statements)

References 80 publications

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“…Additionally, our studies did not define the mechanisms by which the tumor microenvironment mediates the accumulation of microbiota-dependent Vγ6 + and microbiota-independent Vγ4 + subsets that aid tumor growth; it is possible that analogous mechanisms to the Btnl-dependent Vγ7 selection are used ( 26 , 27 , 43 , 44 ). In fact, a recent study has suggested that the expression of Btnl2 by tumor cells can specifically recruit protumorigenic IL-17–producing γδ T cells ( 45 ). Although the reduced number of patients and cells analyzed limit broader generalizations regarding public clones, TCR usage biases, and linked signatures, our analyses of infiltrating γδ T cells in human CRC provide an important parallel for the mechanistic details uncovered in murine studies.…”

Section: Discussionmentioning

confidence: 99%

TCR-Vγδ usage distinguishes protumor from antitumor intestinal γδ T cell subsets

Reis

Darcy

Khan

et al. 2022

Science

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γδ T cells represent a substantial fraction of intestinal lymphocytes at homeostasis, but they also constitute a major lymphocyte population infiltrating colorectal cancers (CRCs); however, their temporal contribution to CRC development or progression remains unclear. Using human CRC samples and murine CRC models, we found that most γδ T cells in premalignant or nontumor colons exhibit cytotoxic markers, whereas tumor-infiltrating γδ T cells express a protumorigenic profile. These contrasting T cell profiles were associated with distinct T cell receptor (TCR)–Vγδ gene usage in both humans and mice. Longitudinal intersectional genetics and antibody-dependent strategies targeting murine γδ T cells enriched in the epithelium at steady state led to heightened tumor development, whereas targeting γδ subsets that accumulate during CRC resulted in reduced tumor growth. Our results uncover temporal pro- and antitumor roles for γδ T cell subsets.

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Section: Discussionmentioning

confidence: 99%

TCR-Vγδ usage distinguishes protumor from antitumor intestinal γδ T cell subsets

Reis

Darcy

Khan

et al. 2022

Science

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“…ADORA2A is an adenosine receptor, and blocking tumor-produced adenosine perhaps enhances the effect of immunotherapy ( Raskovalova et al, 2007 ). BTNL2 is considered an effective inhibitor of the antitumor immune response, which has been confirmed in mouse models ( du et al, 2022 ). The high mRNA level of CD160 in CRC has been confirmed in several studies ( Saleh et al, 2020 ; Ma et al, 2021 ).…”

Section: Discussionmentioning

confidence: 95%

Prognosis analysis of necroptosis-related genes in colorectal cancer based on bioinformatic analysis

Liang

Cheng²,

Chen

et al. 2022

Front. Genet.

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Background: Colorectal cancer (CRC) is one gastrointestinal malignancy, accounting for 10% of cancer diagnoses and cancer-related deaths worldwide each year. Therefore, it is urgent to identify genes involved in CRC predicting the prognosis.Methods: CRC’s data were acquired from the Gene Expression Omnibus (GEO) database (GSE39582 and GSE41258 datasets) and The Cancer Genome Atlas (TCGA) database. The differentially expressed necroptosis-related genes (DENRGs) were sorted out between tumor and normal tissues. Univariate Cox regression analysis and least absolute shrinkage and selectionator operator (LASSO) analysis were applied to selected DENRGs concerning patients’ overall survival and to construct a prognostic biomarker. The effectiveness of this biomarker was assessed by the Kaplan–Meier curve and the receiver operating characteristic (ROC) analysis. The GSE39582 dataset was utilized as external validation for the prognostic signature. Moreover, using univariate and multivariate Cox regression analyses, independent prognostic factors were identified to construct a prognostic nomogram. Next, signaling pathways regulated by the signature were explored through the gene set enrichment analysis (GSEA). The single sample gene set enrichment analysis (ssGSEA) algorithm and tumor immune dysfunction and exclusion (TIDE) were used to explore immune correlation in the two groups, high-risk and low-risk ones. Finally, prognostic genes’ expression was examined in the GSE41258 dataset.Results: In total, 27 DENRGs were filtered, and a necroptosis-related prognostic signature based on 6 DENRGs was constructed, which may better understand the overall survival (OS) of CRC. The Kaplan–Meier curve manifested the effectiveness of the prognostic signature, and the ROC curve showed the same result. In addition, univariate and multivariate Cox regression analyses revealed that age, pathology T, and risk score were independent prognostic factors, and a nomogram was established. Furthermore, the prognostic signature was most significantly associated with the apoptosis pathway. Meanwhile, 24 immune cells represented significant differences between two groups, like the activated B cell. Furthermore, 32 immune checkpoints, TIDE scores, PD-L1 scores, and T-cell exclusion scores were significantly different between the two groups. Finally, a 6-gene prognostic signature represented different expression levels between tumor and normal samples significantly in the GSE41258 dataset.Conclusion: Our study established a signature including 6 genes and a prognostic nomogram that could significantly assess the prognosis of patients with CRC.

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“…Patients in the low-risk category of pancreatic cancer may have comparable resistance mechanisms to those seen in breast cancer, where ICOSLG has been shown to be a possible biomarker for the development of trastuzumab resistance [ 72 ]. New clinical evidence shows that BTNL2 expression is elevated following anti-PD-1 treatment, lending credence to the concept that it may play a crucial role in a novel mechanism of cancer immune escape [ 73 ]. An increase in CTLA4 and PD-1 expression was seen in the low-risk group, and anti-PD-1/PD-L1 antibodies were less effective against pancreatic cancer than they were against melanoma, renal cell carcinoma, and non-small cell lung cancer, owing to immunostasis or drug resistance [ 74 , 75 , 76 ].…”

Section: Discussionmentioning

confidence: 99%

Cuprotosis Programmed-Cell-Death-Related lncRNA Signature Predicts Prognosis and Immune Landscape in PAAD Patients

Chi

Peng

Wang

et al. 2022

Cells

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In terms of mortality and survival, pancreatic cancer is one of the worst malignancies. Known as a unique type of programmed cell death, cuprotosis contributes to tumor cell growth, angiogenesis, and metastasis. Cuprotosis programmed-cell-death-related lncRNAs (CRLs) have been linked to PAAD, although their functions in the tumor microenvironment and prognosis are not well understood. This study included data from the TCGA-PAAD cohort. Random sampling of PAAD data was conducted, splitting the data into two groups for use as a training set and test set (7:3). We searched for differentially expressed genes that were substantially linked to prognosis using univariate Cox and Lasso regression analysis. Through the use of multivariate Cox proportional risk regression, a risk-rating system for prognosis was developed. Correlations between the CRL signature and clinicopathological characteristics, tumor microenvironment, immunotherapy response, and chemotherapy sensitivity were further evaluated. Lastly, qRT-PCR was used to compare CRL expression in healthy tissues to that in tumors. Some CRLs are thought to have strong correlations with PAAD outcomes. These CRLs include AC005332.6, LINC02041, LINC00857, and AL117382.1. The CRL-based signature construction exhibited outstanding predictive performance and offers a fresh approach to evaluating pre-immune effectiveness, paving the way for future studies in precision immuno-oncology.

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Cancer cell-expressed BTNL2 facilitates tumour immune escape via engagement with IL-17A-producing γδ T cells

Cited by 24 publications

References 80 publications

TCR-Vγδ usage distinguishes protumor from antitumor intestinal γδ T cell subsets

TCR-Vγδ usage distinguishes protumor from antitumor intestinal γδ T cell subsets

Prognosis analysis of necroptosis-related genes in colorectal cancer based on bioinformatic analysis

Cuprotosis Programmed-Cell-Death-Related lncRNA Signature Predicts Prognosis and Immune Landscape in PAAD Patients

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