scholarly journals Topical Application of Temperature-Sensitive Gel Containing Caerin 1.1 and 1.9 Peptides on TC-1 Tumour-Bearing Mice Induced High-Level Immune Response in the Tumour Microenvironment

2021 ◽  
Vol 11 ◽  
Author(s):  
Guoying Ni ◽  
Xiaosong Liu ◽  
Hejie Li ◽  
Conor E. Fogarty ◽  
Shu Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Topical Application ◽  
Immune Activation ◽  
Tumour Microenvironment ◽  
Temperature Sensitive ◽  
Hpv16 E6 ◽  
Tumour Bearing ◽  
Associated Lesions ◽  
High Level

The development of topical cream drugs that increase the immune activation of tumour-infiltrating lymphocytes against tumour and chronic viral infection-associated lesions is of great immunotherapeutic significance. This study demonstrates that the topical application of a temperature-sensitive gel containing caerin 1.1 and 1.9 peptides reduces nearly 50% of the tumour weight of HPV16 E6/E7-transformed TC-1 tumour-bearing mice via improving the tumour microenvironment. Confocal microscopy confirms the time-dependent penetration of caerin 1.9 through the epidermal layer of the ear skin structure of mice. Single-cell transcriptomic analysis shows that the caerin 1.1/1.9 gel expands the populations with high immune activation level and largely stimulates the pro-inflammatory activity of NK and dendritic cells. Closely associated with INFα response, Cebpb seems to play a key role in altering the function of all Arg1hi macrophages in the caerin group. In addition, the caerin gel treatment recruits almost two-fold more activated CD8+ T cells to the TME, relative to the untreated tumour, which shows a synergistic effect derived from the regulation of S1pr1, Ccr7, Ms4a4b and Gimap family expression. The TMT10plex-labelling proteomic quantification further demonstrates the activation of interferon-alpha/beta secretion and response to cytokine stimulus by the caerin gel, while the protein contents of several key regulators were elevated by more than 30%, such as Cd5l, Gzma, Ifit1, Irf9 and Stat1. Computational integration of the proteome with the single-cell transcriptome consistently suggested greater activation of NK and T cells with the topical application of caerin peptide gel.

scholarly journals Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers

Nature ◽  
2021 ◽  
Author(s):  
Justina X. Caushi ◽  
Jiajia Zhang ◽  
Zhicheng Ji ◽  
Ajay Vaghasia ◽  
Boyang Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
T Cell Receptors ◽  
Tumour Microenvironment ◽  
Lung Cancers ◽  
Cell Receptors ◽  
Interleukin 7

AbstractPD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a ‘barcode’ to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein–Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.

scholarly journals Intra-tumoral injection of caerin 1.1 and 1.9 peptides in vaccinated TC-1 tumour bearing mice with PD-1 blockade modulates macrophage heterogeneity and the activation of CD8+ T cells in the tumour microenvironment

2020 ◽  
Author(s):  
Guoying Ni ◽  
Xiaolian Wu ◽  
Ying Liu ◽  
Hejie Li ◽  
Shu Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Effector Memory ◽  
Proteomic Profiling ◽  
T Subsets ◽  
Cell Transcriptome

Abstract Development of a vaccine formula that alters the tumour-infiltrating lymphocytes to be more immune active against a tumour is key to the improvement of clinical responses to immunotherapy. Here, we demonstrate that, in conjunction with E7 antigen specific immunotherapy, and IL-10 and PD-1 blockade, intra-tumoral administration of caerin 1.1 and 1.9 peptides further improves the tumour microenvironment (TME) when compared with injection of a control peptide. We used single cell transcriptomics and mass spectrometry-based proteomics to quantify changes in cellular activity across different cell types within the TME. We show that the injection of caerin 1.1/1.9 increases immune activating macrophages and NK cells, while reducing immunosuppressive macrophages with M2 phenotype, and increased numbers of activated CD8+ T cells with higher populations of memory and effector-memory CD8+ T subsets. Proteomic profiling demonstrated activation of Stat1 modulated apoptosis and production of nitric oxide. Further, computational integration of the proteome with the single cell transcriptome was consistent with deactivation of immune suppressive B cell function following caerin 1.1 and 1.9 treatment.

scholarly journals The Dosage of the Derivative ofClostridium Ghonii(DCG) Spores Dictates Whether an IFNγ/IL-9 or a Strong IFNγResponse Is Elicited in TC-1 Tumour Bearing Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Guoying Ni ◽  
Yong Wang ◽  
David Good ◽  
Jianwei Yuan ◽  
Xuan Pan ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Tumour Microenvironment ◽  
T Cell Response ◽  
Tumour Regression ◽  
Spleen Cells ◽  
Human Papillomavirus 16 ◽  
Tumour Bearing ◽  
Immune Mediated

Background. AnaerobicClostridialspores (CG) cause significant oncolysis in hypoxic tumour microenvironment and result in tumour regression in both animal models and clinical trials. The immune mediated response plays a critical role in the antitumour effect by the anaerobic spore treatment.Method. Human papillomavirus 16 E6/E7 transformed TC-1 tumour bearing mice were intravenously administered with low (1 × 108CFU/kg) or high dosage (3 × 108CFU/kg) of DerivativeClostridialspore (DCG).Results. Intravenous administration of the derivative ofClostridial ghonii(DCG) spores leads to both tumour and systemic inflammatory responses characterized by increased IFNγ/IL-9 secreting T cells in the spleen and the tumour. Low numbers of antigen specific T cells (<20/106spleen cells) in the spleen of the tumour bearing mice are also detected after intravenous DCG delivery. Interestingly, our results showed that a mixed IL-9/IFNγsecreting T cell response was induced when the tumour bearing mice received a low dose of DCG spore (1 × 108CFU/kg), while a strong IFNγresponse was elicited with a high dosage of DCG spore (3 × 108CFU/kg).Conclusion. The dosage of DCG spore will determine the types of the DCG induced immune responses.

scholarly journals Immune responses in pancreatic cancer may be restricted by prevalence of activated regulatory T-cells, dysfunctional and senescent T-cells

2020 ◽  
Author(s):  
Shivan Sivakumar ◽  
Enas Abu-Shah ◽  
David J Ahern ◽  
Edward H Arbe-Barnes ◽  
Nagina Mangal ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Regulatory T Cell ◽  
Rational Design ◽  
Tumour Microenvironment ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma

AbstractObjectivePancreatic cancer has the worst prognosis of any human malignancy and leukocyte infiltration is a major prognostic marker of the disease. As current immunotherapies confer negligible survival benefits, there is a need to better characterise leukocytes in pancreatic cancer to identify better therapeutic strategies.DesignIn this study, a multi-parameter mass-cytometry analysis was performed on 32,000 T-cells from eight human pancreatic cancer patients. Single-cell RNA sequencing dataset analysis was performed on a cohort of 24 patients. Multiplex immunohistochemistry imaging and spatial analysis were performed to map immune infiltration into the tumour microenvironment.ResultsRegulatory T-cell populations demonstrated highly immunosuppressive states with high TIGIT, ICOS and CD39 expression. CD8+ T-cells were found to be either in senescence or an exhausted state. The exhausted CD8 T-cells had low PD-1 expression but high TIGIT and CD39 expression. These findings were corroborated in an independent pancreatic cancer single-cell RNA dataset from 24 patients.ConclusionsThese data suggest that T-cells are major players in the suppressive microenvironment of pancreatic cancer. Our work identifies novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma.Statement of SignificanceThis study elucidates the T-cell phenotypes in pancreatic ductal adenocarcinoma (PDAC). T-cells potentiate immune-suppression through an activated regulatory T-cell population expressing high TIGIT, ICOS and CD39. CD8+ T-cells were primarily senescent or TIGIT+ exhausted, but with minimal PD-1 expression. These findings propose new immunotherapy targets for PDAC.

scholarly journals Single-cell transcriptomic analyses of T cells in chronic HCV-infected patients dominated by DAA-induced interferon signaling changes

2021 ◽  
Vol 17 (8) ◽  
pp. e1009799
Author(s):  
Matthew A. Burchill ◽  
Matthew P. Salomon ◽  
Lucy Golden-Mason ◽  
Amanda Wieland ◽  
Ana C. Maretti-Mira ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Immune Activation ◽  
Cell Function ◽  
Innate Immune ◽  
T Cell Subsets ◽  
Interferon Signaling ◽  
Direct Acting Antiviral ◽  
Chronic Hcv

Chronic infection with HCV is manifested by dysregulation of innate immune responses and impaired T cell function at multiple levels. These changes may impact susceptibility to other infections, responsiveness to antiviral therapies, vaccine responsiveness, and development of complications such as hepatocellular carcinoma. Highly effective direct-acting antiviral (DAA) therapy has revolutionized the management of chronic HCV, with expected cure rates exceeding 95%. DAA treatment represents a unique opportunity to investigate to what extent elimination of viral replication and chronic antigen stimulation can restore immunologic phenotype. In this study we interrogated the global transcriptional profile of isolated peripheral blood T cells before, during and after IFN-free DAA therapy using single-cell mRNA sequencing. Our results demonstrate that T cells mapped at single-cell resolution have dramatic transcriptomic changes early after initiation of DAA and many of these changes are sustained after completion of DAA therapy. Specifically, we see a significant reduction in transcripts associated with innate immune activation and interferon signaling such as ISG15, ISG20, IFIT3, OAS and MX1 in many different T cell subsets. Furthermore, we find an early upregulation of a gene involved in suppression of immune activation, DUSP1, in circulating T cells. Conclusion: This study provides the first in-depth transcriptomic analysis at the single-cell level of patients undergoing DAA therapy, demonstrating that IFN-free antiviral therapy in chronic HCV infection induces hitherto unrecognized shifts in innate immune and interferon signaling within T cell populations early, during, and long-term after treatment. The present study provides a rich data source to explore the effects of DAA treatment on bulk T cells.

scholarly journals Activated Regulatory T-Cells, Dysfunctional and Senescent T-Cells Hinder the Immunity in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1776
Author(s):  
Shivan Sivakumar ◽  
Enas Abu-Shah ◽  
David J. Ahern ◽  
Edward H. Arbe-Barnes ◽  
Ashwin K. Jainarayanan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Rational Design ◽  
Tumour Microenvironment ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Human Malignancy ◽  
New Generation

Pancreatic cancer has one of the worst prognoses of any human malignancy and leukocyte infiltration is a major prognostic marker of the disease. As current immunotherapies confer negligible survival benefits, there is a need to better characterise leukocytes in pancreatic cancer to identify better therapeutic strategies. In this study, we analysed 32 human pancreatic cancer patients from two independent cohorts. A multi-parameter mass-cytometry analysis was performed on 32,000 T-cells from eight patients. Single-cell RNA sequencing dataset analysis was performed on a cohort of 24 patients. Multiplex immunohistochemistry imaging and spatial analysis were performed to map immune infiltration into the tumour microenvironment. Regulatory T-cell populations demonstrated highly immunosuppressive states with high TIGIT, ICOS and CD39 expression. CD8+ T-cells were found to be either in senescence or an exhausted state. The exhausted CD8 T-cells had low PD-1 expression but high TIGIT and CD39 expression. These findings were corroborated in an independent pancreatic cancer single-cell RNA dataset. These data suggest that T-cells are major players in the suppressive microenvironment of pancreatic cancer. Our work identifies multiple novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma.

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