Intratumoral CD4+ T cells mediate anti-tumor cytotoxicity in human bladder cancer
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ABSTRACT:
PROVIDER: PRJNA629542 | ENA |
REPOSITORIES: ENA
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Project description:Responses to anti-PD-1 immunotherapy occur but are infrequent in bladder cancer. The specific T cells that mediate tumor rejection are unknown. T cells from human bladder tumors and non-malignant tissue were assessed with single-cell RNA and paired T cell receptor (TCR) sequencing of 30,604 T cells from 7 patients. We find that the states and repertoire of CD8+ T cells are not altered in tumors compared with non-malignant tissues. In contrast, single-cell analysis of CD4+ T cells demonstrates several tumor-specific states, including multiple distinct states of regulatory T cells. Surprisingly, we also find multiple cytotoxic CD4+ T cell states that are clonally expanded. These CD4+ T cells can kill autologous tumor in an MHC class II-dependent fashion and are suppressed by regulatory T cells. Further, a gene signature of cytotoxic CD4+ T cells in tumors predicts a clinical response in 244 metastatic bladder cancer patients treated with anti-PD-L1.
2020-06-01 | GSE149652 | GEO
Project description:Responses to anti-PD-1 immunotherapy occur but are infrequent in bladder cancer. The specific T cells that mediate tumor rejection are unknown. T cells from human bladder tumors and non-malignant tissue were assessed with single-cell RNA and paired T cell receptor (TCR) sequencing of 30,604 T cells from 7 patients. We find that the states and repertoires of CD8+ T cells are not distinct in tumors compared with non-malignant tissues. In contrast, single-cell analysis of CD4+ T cells demonstrates several tumor-specific states, including multiple distinct states of regulatory T cells. Surprisingly, we also find multiple cytotoxic CD4+ T cell states that are clonally expanded. These CD4+ T cells can kill autologous tumors in an MHC class II-dependent fashion and are suppressed by regulatory T cells. Further, a gene signature of cytotoxic CD4+ T cells in tumors predicts a clinical response in 244 metastatic bladder cancer patients treated with anti-PD-L1.
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Project description:Background: Frankincense (Ru Xiang) and sandalwood (Tan Xiang) are ingredients used in traditional Chinese medicine, and have been recognized as cancer preventive and therapeutic agents. Hydrodistillation of frankincense gum resins and sandalwood heartwood to prepare essential oils is a method to extract biologically active ingredients from these plant-derived products. This study was designed to differentiate frankincense (Boswellia carterii) and sandalwood (Santalum album) induced anti-proliferative and pro-apoptotic activities in cultured human bladder cancer cells. Methods: Frankincense and sandalwood essential oils-mediated cytotoxicity was studied in established human bladder cancer J82 cells and immortalized normal human bladder urothelial UROtsa cells using a colorimetric assay. Essential oils-activated gene expression and pathway activation in human bladder cancer J82 cells were identified using high density microarray and bioinformatics techniques. Results: Human bladder cancer cells were more sensitive to immortalized normal bladder cells with suppressed viability following frankincense essential oil exposure. In contrast, both cancerous and normal bladder cells responded to sandalwood essential with similar levels of cytotoxicity. Based on microarray and bioinformatics analyses, genes responsible for suppressing biological processes and apoptosis were induced in J82 cells by both essential oils. Although both frankincense and sandalwood essential oils activated common ontologies and canonical pathways leading to suppressed J82 cell viability and apoptosis, each essential oil had unique property on these cells. For example, heat shock proteins and histone core were ongologies regulated by frankincense essential oil, whereas transcription regulation and G-protein couple receptor were ontologies unique to sandalwood essential oil treatment. In addition, NRF-2 mediated oxidative stress was implicated as the primary cause of frankincense essential oil-induced J82 cell death; in contrast, DNA damage and cell cycle arrest might be attributed to sandalwood essential oil-mediated cytotoxicity. Conclusion: Based on cell biology and comprehensive gene expression analysis, our results provide a preliminary, yet focused characterization of genetic responses to frankincense and sandalwood essential oils with respect to their proposed anti-neoplastic properties. Modern biomedical technologies are powerful tools to study biological responses following treatments with traditional Chinese medicine, which always consist of complex chemical constituents. To differentiate mechanisms of frankincense and sandalwood essential oils induced cytotoxicty in bladder cancer J82 cells, time-dependent transcriptoms expression was performed in cultured cells following essential oils treatments
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Project description:While cytotoxic CD4+ tumor-infiltrating lymphocytes have anti-cancer activity in patients, whether these can be non-invasively monitored and how these are regulated remains obscure. By matching single cells with T cell receptors (TCR) in tumor and blood of bladder cancer patients, we identified distinct pools of tumor-matching cytotoxic CD4+ T cells in the periphery directly reflecting the predominant antigenic specificities of intratumoral CD4+ TILs. On one hand, the granzyme B (GZMB)-expressing cytotoxic CD4+ subset proliferated in blood in response to PD-1 blockade, but was separately regulated by the killer cell lectin-like receptor G1 (KLRG1) which inhibited their killing by interacting with E-cadherin. Conversely, a clonally related, granzyme K (GZMK)-expressing circulating CD4+ population demonstrated basal proliferation and a memory phenotype that may result from activation of GZMB+ cells, but was not directly mobilized by PD-1 blockade. As KLRG1 marked the majority of circulating tumor TCR-matched cytotoxic CD4+ T cells, this work nominates KLRG1 as a means to isolate them from blood and provide a window into intratumoral CD4+ recognition, as well as a putative regulatory receptor to mobilize the cytolytic GZMB+ subset for therapeutic benefit. Our findings also underscore the ontogenic relationship of GZMB- and GZMK-expressing populations and the distinct cues that regulate their activity.
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