ORCID Profile
0000-0002-0659-5944
Current Organisations
Politecnico di Milano
,
Weatherall Institute of Molecular Medicine
,
University of Oxford
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Publisher: Cold Spring Harbor Laboratory
Date: 16-11-2020
DOI: 10.1101/2020.11.15.383786
Abstract: Immune checkpoint blockers (ICB) exert their anti-cancer effects via CD8 + T cells, although how responses vary over sub-populations and across clones is incompletely understood. We performed single-cell RNA-sequencing of CD8 + T cells and their receptors pre- and post-ICB across eight patients, integrating results with bulk-sequencing data (n=209). We identify seven subsets with ergent responses to ICB, finding the effector cluster demonstrates the most pronounced changes. Likewise, transcriptomic response to ICB relates to clone size, with large clones demonstrating increased numbers of regulated genes of higher immunological pertinence. Cytotoxic effector clones were more likely to persist long-term following ICB and overlapped with public tumour-infiltrating lymphocyte clonotypes. Notably, pre-treatment CD8 + cytotoxicity associated with progression-free survival, highlighting the importance of the baseline CD8 + immune landscape in long-term response. This work further advances understanding of the molecular determinants of ICB response and assists in the search for peripheral prognostic biomarkers. Using single-cell and bulk RNA sequencing we explore checkpoint immunotherapy activity on peripheral CD8 + T cells in metastatic melanoma demonstrating that cell subset and clone size determine gene expression responses to treatment, and that pre-treatment cytotoxicity and clonality of peripheral CD8 + T cells is clinically prognostic.
Publisher: Research Square Platform LLC
Date: 12-04-2022
DOI: 10.21203/RS.3.RS-1531341/V1
Abstract: Although treatment with immune checkpoint blockade (ICB) has transformed outcomes for patients with melanoma (1, 2), it frequently triggers immune related adverse events (irAEs), causing serious morbidity and presenting a major hurdle to immuno-oncology (3, 4). The degree to which germline genetic variation predisposes to irAEs is unknown. Here, studying a cohort of 214 patients receiving ICB for melanoma, we observe increased risk of severe irAEs in carriers of the minor allele of rs16906115, intronic to IL7. We find rs16906115 forms a B cell specific expression quantitative trait locus to IL7 in patients only, with risk allele carriers demonstrating increased B cell IL7 expression, immunoglobulin class switching and somatic hypermutation. Notably, increased B cell IL7 expression is independently associated with risk of irAEs. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB induced CD8+ T cell subset responses, with allelic effects on gene expression and clonality. Risk allele carriers display significantly reduced CD8+ T cell mitotic responses to ICB, with skewing of T cell clonality and increased counts of large clones previously associated with disease response. These observations highlight key roles for both B cells and IL-7 in ICB response and toxicity, and demonstrate the power of agnostic human genetic studies to reveal novel determinants of response to cancer immunotherapy.
Publisher: Public Library of Science (PLoS)
Date: 19-04-2021
DOI: 10.1371/JOURNAL.PPAT.1009522
Abstract: Although HIV infection inhibits interferon responses in its target cells in vitro , interferon signatures can be detected in vivo soon after sexual transmission, mainly attributed to plasmacytoid dendritic cells (pDCs). In this study, we examined the physiological contributions of pDCs to early HIV acquisition using coculture models of pDCs with myeloid DCs, macrophages and the resting central, transitional and effector memory CD4 T cell subsets. pDCs impacted infection in a cell-specific manner. In myeloid cells, HIV infection was decreased via antiviral effects, cell maturation and downregulation of CCR5 expression. In contrast, in resting memory CD4 T cells, pDCs induced a subset-specific increase in intracellular HIV p24 protein expression without any activation or increase in CCR5 expression, as measured by flow cytometry. This increase was due to reactivation rather than enhanced viral spread, as blocking HIV entry via CCR5 did not alter the increased intracellular p24 expression. Furthermore, the load and proportion of cells expressing HIV DNA were restricted in the presence of pDCs while reverse transcriptase and p24 ELISA assays showed no increase in particle associated reverse transcriptase or extracellular p24 production. In addition, pDCs also markedly induced the expression of CD69 on infected CD4 T cells and other markers of CD4 T cell tissue retention. These phenotypic changes showed marked parallels with resident memory CD4 T cells isolated from anogenital tissue using enzymatic digestion. Production of IFNα by pDCs was the main driving factor for all these results. Thus, pDCs may reduce HIV spread during initial mucosal acquisition by inhibiting replication in myeloid cells while reactivating latent virus in resting memory CD4 T cells and retaining them for immune clearance.
Publisher: Springer Science and Business Media LLC
Date: 12-2022
DOI: 10.1038/S41591-022-02095-5
Abstract: Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7 . We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, ergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8 + T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma.
Publisher: Research Square Platform LLC
Date: 27-07-2021
DOI: 10.21203/RS.3.RS-734011/V1
Abstract: NP 105-113 -B*07:02 specific CD8 + T-cell responses are considered among the most dominant in SARS-CoV-2-infected in iduals. We found strong association of this response with mild disease. Analysis of NP 105-113 -B*07:02 specific T-cell clones and single cell sequencing were performed concurrently, with functional avidity and anti-viral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with TCR usage, transcriptome signature, and disease severity (acute N=77, convalescent N=52). We demonstrated a beneficial association of NP 105-113 -B*07:02 specific T-cells in COVID-19 disease progression, linked with expansion of T-cell precursors, high functional avidity and anti-viral effector function. Broad immune memory pools were narrowed post-infection but NP 105-113 -B*07:02 specific T-cells were maintained 6 months after infection with preserved anti-viral efficacy to the SARS-CoV-2 Victoria strain, as well as new Alpha, Beta and Gamma variants. Our data shows that NP 105-113 -B*07:02 specific T-cell responses associate with mild disease and high anti-viral efficacy, pointing to inclusion for future vaccine design.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2023
DOI: 10.1038/S41467-023-35948-9
Abstract: IFNγ is an immune mediator with concomitant pro- and anti-tumor functions. Here, we provide evidence that IFNγ directly acts on intra-tumoral CD8 T cells to restrict anti-tumor responses. We report that expression of the IFNγ receptor β chain (IFNγR2) in CD8 T cells negatively correlates with clinical responsiveness to checkpoint blockade in metastatic melanoma patients, suggesting that the loss of sensitivity to IFNγ contributes to successful antitumor immunity. Indeed, specific deletion of IFNγR in CD8 T cells promotes tumor control in a mouse model of melanoma. Chronic IFNγ inhibits the maintenance, clonal ersity and proliferation of stem-like T cells. This leads to decreased generation of T cells with intermediate expression of exhaustion markers, previously associated with beneficial anti-tumor responses. This study provides evidence of a negative feedback loop whereby IFNγ depletes stem-like T cells to restrict anti-tumor immunity. Targeting this pathway might represent an alternative strategy to enhance T cell-based therapies.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2022
DOI: 10.1038/S41467-022-31626-4
Abstract: Natural Killer cells are innate lymphocytes with central roles in immunosurveillance and are implicated in autoimmune pathogenesis. The degree to which regulatory variants affect Natural Killer cell gene expression is poorly understood. Here we perform expression quantitative trait locus mapping of negatively selected Natural Killer cells from a population of healthy Europeans ( n = 245). We find a significant subset of genes demonstrate expression quantitative trait loci specific to Natural Killer cells and these are highly informative of human disease, in particular autoimmunity. A Natural Killer cell transcriptome-wide association study across five common autoimmune diseases identifies further novel associations at 27 genes. In addition to these cis observations, we find novel master-regulatory regions impacting expression of trans gene networks at regions including 19q13.4, the Killer cell Immunoglobulin-like Receptor region, GNLY , MC1R and UVSSA . Our findings provide new insights into the unique biology of Natural Killer cells, demonstrating markedly different expression quantitative trait loci from other immune cells, with implications for disease mechanisms.
Publisher: American Society for Clinical Investigation
Date: 04-2022
DOI: 10.1172/JCI154422
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1038/S41590-021-01084-Z
Abstract: NP 105–113 -B*07:02-specific CD8 + T cell responses are considered among the most dominant in SARS-CoV-2-infected in iduals. We found strong association of this response with mild disease. Analysis of NP 105–113 -B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP 105–113 -B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP 105–113 -B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP 105–113 -B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.
Publisher: Frontiers Media SA
Date: 16-05-2019
Publisher: Frontiers Media SA
Date: 24-09-2019
Publisher: Springer Science and Business Media LLC
Date: 21-06-2019
DOI: 10.1038/S41467-019-10697-W
Abstract: Langerhans cells (LC) are thought to be the only mononuclear phagocyte population in the epidermis where they detect pathogens. Here, we show that CD11c + dendritic cells (DCs) are also present. These cells are transcriptionally similar to dermal cDC2 but are more efficient antigen-presenting cells. Compared to LCs, epidermal CD11c + DCs are enriched in anogenital tissues where they preferentially interact with HIV, express the higher levels of HIV entry receptor CCR5, support the higher levels of HIV uptake and replication and are more efficient at transmitting the virus to CD4 T cells. Importantly, these findings are observed using both a lab-adapted and transmitted/founder strain of HIV. We also describe a CD33 low cell population, which is transcriptionally similar to LCs but does not appear to function as antigen-presenting cells or acts as HIV target cells. Our findings reveal that epidermal DCs in anogenital tissues potentially play a key role in sexual transmission of HIV.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 29-10-2021
DOI: 10.1126/SCIIMMUNOL.ABJ8825
Abstract: The cytotoxicity and clone size of CD8 + T cell pretreatment are prognostic for immune checkpoint blockade.
Publisher: MDPI AG
Date: 10-2019
DOI: 10.3390/APP9194100
Abstract: Foot strike mode and footwear features are known to affect ankle joint kinematics and loading patterns, but how those factors are related to the ankle dynamic properties is less clear. In our study, two distinct s les of experienced long-distance runners: habitual rearfoot strikers (n = 10) and habitual forefoot strikers (n = 10), were analysed while running at constant speed on an instrumented treadmill in three footwear conditions. The joint dynamic stiffness was analysed for three subphases of the moment–angle plot: early rising, late rising and descending. Habitual rearfoot strikers displayed a statistically (p 0.05) higher ankle dynamic stiffness in all combinations of shoes and subphases, except in early stance in supportive shoes. In minimal-supportive shoes, both groups had the lowest dynamic stiffness values for early and late rising (initial contact through mid-stance), whilst the highest stiffness values were at late rising in minimal shoes for both rearfoot and forefoot strikers (0.21 ± 0.04, 0.24 ± 0.06 (Nm/kg/°∙100), respectively). In conclusion, habitual forefoot strikers may have access to a wider physiological range of the muscle torque and joint angle. This increased potential may allow forefoot strikers to adapt to different footwear by regulating ankle dynamic stiffness depending upon the motor task.
Publisher: Elsevier BV
Date: 08-2020
Publisher: Elsevier BV
Date: 03-2022
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Orion Tong.