ORCID Profile
0000-0002-3531-2464
Current Organisations
University of Oxford
,
Oxford University Hospitals NHS Trust
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Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543768.V1
Abstract: Movie S3 shows CD103- T cell killing HCT116 cancer cell, in brighfield imaging.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543774
Abstract: Movie S1 shows CD103+ T cell killing HCT116 cancer cell, in brighfield imaging.
Publisher: Cold Spring Harbor Laboratory
Date: 11-05-2021
DOI: 10.1101/2021.05.11.21256877
Abstract: Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1 38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543995
Abstract: Supplementary Figure 1 to 7, Supplementary Table 1
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543998
Abstract: Supplemental Figure Legends
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543774.V1
Abstract: Movie S1 shows CD103+ T cell killing HCT116 cancer cell, in brighfield imaging.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543771
Abstract: Movie S2 shows CD103+ T cell killing HCT116 cancer cell, by calcium flux imaging.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543995.V1
Abstract: Supplementary Figure 1 to 7, Supplementary Table 1
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6550399
Abstract: Abstract Enrichment of CD103 sup + /sup tumor-infiltrating T lymphocytes (TIL) is associated with improved outcomes in patients. However, the characteristics of human CD103 sup + /sup cytotoxic CD8 sup + /sup T cells (CTL) and their role in tumor control remain unclear. We investigated the features and antitumor mechanisms of CD103 sup + /sup CTLs by assessing T-cell receptor (TCR)–matched CD103 sup + /sup and CD103 sup − /sup cancer-specific CTL immunity i in vitro /i and its immunophenotype i ex vivo /i . Interestingly, we found that differentiated CD103 sup + /sup cancer-specific CTLs expressed the active form of TGFβ1 to continually self-regulate CD103 expression, without relying on external TGFβ1-producing cells. The presence of CD103 on CTLs improved TCR antigen sensitivity, which enabled faster cancer recognition and rapid antitumor cytotoxicity. These CD103 sup + /sup CTLs had elevated energetic potential and faster migration capacity. However, they had increased inhibitory receptor coexpression and elevated T-cell apoptosis following prolonged cancer exposure. Our data provide fundamental insights into the properties of matured human CD103 sup + /sup cancer-specific CTLs, which could have important implications for future designs of tissue-localized cancer immunotherapy strategies. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6550497
Abstract: Abstract Immunotherapy treatments with anti-PD-1 boost recovery in less than 30% of treated cancer patients, indicating the complexity of the tumor microenvironment. Expression of HLA-E is linked to poor clinical outcomes in mice and human patients. However, the contributions to immune evasion of HLA-E, a ligand for the inhibitory CD94/NKG2A receptor, when expressed on tumors, compared with adjacent tissue and peripheral blood mononuclear cells, remains unclear. In this study, we report that epithelial-derived cancer cells, tumor macrophages, and CD141 sup + /sup conventional dendritic cells (cDC) contributed to HLA-E enrichment in carcinomas. Different cancer types showed a similar pattern of enrichment. Enrichment correlated to NKG2A upregulation on CD8 sup + /sup tumor-infiltrating T lymphocytes (TIL) but not on CD4 sup + /sup TILs. CD94/NKG2A is exclusively expressed on PD-1 sup high /sup TILs while lacking intratumoral CD103 expression. We also found that the presence of CD94/NKG2A on human tumor–specific T cells impairs IL2 receptor–dependent proliferation, which affects IFNγ-mediated responses and antitumor cytotoxicity. These functionalities recover following antibody-mediated blockade i in vitro /i and i ex vivo /i . Our results suggest that enriched HLA-E:CD94/NKG2A inhibitory interaction can impair survival of PD-1 sup high /sup TILs in the tumor microenvironment. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543759
Abstract: Titles and Legends for Movies 1-4
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543762
Abstract: Supplementary Figures and Tables
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543765
Abstract: Movie S4 shows CD103- T cell killing HCT116 cancer cell, by calcium flux imaging.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6550399.V1
Abstract: Abstract Enrichment of CD103 sup + /sup tumor-infiltrating T lymphocytes (TIL) is associated with improved outcomes in patients. However, the characteristics of human CD103 sup + /sup cytotoxic CD8 sup + /sup T cells (CTL) and their role in tumor control remain unclear. We investigated the features and antitumor mechanisms of CD103 sup + /sup CTLs by assessing T-cell receptor (TCR)–matched CD103 sup + /sup and CD103 sup − /sup cancer-specific CTL immunity i in vitro /i and its immunophenotype i ex vivo /i . Interestingly, we found that differentiated CD103 sup + /sup cancer-specific CTLs expressed the active form of TGFβ1 to continually self-regulate CD103 expression, without relying on external TGFβ1-producing cells. The presence of CD103 on CTLs improved TCR antigen sensitivity, which enabled faster cancer recognition and rapid antitumor cytotoxicity. These CD103 sup + /sup CTLs had elevated energetic potential and faster migration capacity. However, they had increased inhibitory receptor coexpression and elevated T-cell apoptosis following prolonged cancer exposure. Our data provide fundamental insights into the properties of matured human CD103 sup + /sup cancer-specific CTLs, which could have important implications for future designs of tissue-localized cancer immunotherapy strategies. /
Publisher: American Association for Cancer Research (AACR)
Date: 08-2019
DOI: 10.1158/2326-6066.CIR-18-0885
Abstract: Immunotherapy treatments with anti-PD-1 boost recovery in less than 30% of treated cancer patients, indicating the complexity of the tumor microenvironment. Expression of HLA-E is linked to poor clinical outcomes in mice and human patients. However, the contributions to immune evasion of HLA-E, a ligand for the inhibitory CD94/NKG2A receptor, when expressed on tumors, compared with adjacent tissue and peripheral blood mononuclear cells, remains unclear. In this study, we report that epithelial-derived cancer cells, tumor macrophages, and CD141+ conventional dendritic cells (cDC) contributed to HLA-E enrichment in carcinomas. Different cancer types showed a similar pattern of enrichment. Enrichment correlated to NKG2A upregulation on CD8+ tumor-infiltrating T lymphocytes (TIL) but not on CD4+ TILs. CD94/NKG2A is exclusively expressed on PD-1high TILs while lacking intratumoral CD103 expression. We also found that the presence of CD94/NKG2A on human tumor–specific T cells impairs IL2 receptor–dependent proliferation, which affects IFNγ-mediated responses and antitumor cytotoxicity. These functionalities recover following antibody-mediated blockade in vitro and ex vivo. Our results suggest that enriched HLA-E:CD94/NKG2A inhibitory interaction can impair survival of PD-1high TILs in the tumor microenvironment.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543765.V1
Abstract: Movie S4 shows CD103- T cell killing HCT116 cancer cell, by calcium flux imaging.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543771.V1
Abstract: Movie S2 shows CD103+ T cell killing HCT116 cancer cell, by calcium flux imaging.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543768
Abstract: Movie S3 shows CD103- T cell killing HCT116 cancer cell, in brighfield imaging.
Publisher: American Association for Cancer Research (AACR)
Date: 02-2020
DOI: 10.1158/2326-6066.CIR-19-0554
Abstract: Enrichment of CD103+ tumor-infiltrating T lymphocytes (TIL) is associated with improved outcomes in patients. However, the characteristics of human CD103+ cytotoxic CD8+ T cells (CTL) and their role in tumor control remain unclear. We investigated the features and antitumor mechanisms of CD103+ CTLs by assessing T-cell receptor (TCR)–matched CD103+ and CD103− cancer-specific CTL immunity in vitro and its immunophenotype ex vivo. Interestingly, we found that differentiated CD103+ cancer-specific CTLs expressed the active form of TGFβ1 to continually self-regulate CD103 expression, without relying on external TGFβ1-producing cells. The presence of CD103 on CTLs improved TCR antigen sensitivity, which enabled faster cancer recognition and rapid antitumor cytotoxicity. These CD103+ CTLs had elevated energetic potential and faster migration capacity. However, they had increased inhibitory receptor coexpression and elevated T-cell apoptosis following prolonged cancer exposure. Our data provide fundamental insights into the properties of matured human CD103+ cancer-specific CTLs, which could have important implications for future designs of tissue-localized cancer immunotherapy strategies.
Publisher: Springer Science and Business Media LLC
Date: 10-03-2022
DOI: 10.1038/S41467-022-28898-1
Abstract: The trajectories of acquired immunity to severe acute respiratory syndrome coronavirus 2 infection are not fully understood. We present a detailed longitudinal cohort study of UK healthcare workers prior to vaccination, presenting April-June 2020 with asymptomatic or symptomatic infection. Here we show a highly variable range of responses, some of which (T cell interferon-gamma ELISpot, N-specific antibody) wane over time, while others (spike-specific antibody, B cell memory ELISpot) are stable. We use integrative analysis and a machine-learning approach (SIMON - Sequential Iterative Modeling OverNight) to explore this heterogeneity. We identify a subgroup of participants with higher antibody responses and interferon-gamma ELISpot T cell responses, and a robust trajectory for longer term immunity associates with higher levels of neutralising antibodies against the infecting (Victoria) strain and also against variants B.1.1.7 (alpha) and B.1.351 (beta). These variable trajectories following early priming may define subsequent protection from severe disease from novel variants.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543998.V1
Abstract: Supplemental Figure Legends
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543759.V1
Abstract: Titles and Legends for Movies 1-4
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543762.V1
Abstract: Supplementary Figures and Tables
Publisher: Springer Science and Business Media LLC
Date: 17-08-2021
DOI: 10.1038/S41467-021-25167-5
Abstract: The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6550497.V1
Abstract: Abstract Immunotherapy treatments with anti-PD-1 boost recovery in less than 30% of treated cancer patients, indicating the complexity of the tumor microenvironment. Expression of HLA-E is linked to poor clinical outcomes in mice and human patients. However, the contributions to immune evasion of HLA-E, a ligand for the inhibitory CD94/NKG2A receptor, when expressed on tumors, compared with adjacent tissue and peripheral blood mononuclear cells, remains unclear. In this study, we report that epithelial-derived cancer cells, tumor macrophages, and CD141 sup + /sup conventional dendritic cells (cDC) contributed to HLA-E enrichment in carcinomas. Different cancer types showed a similar pattern of enrichment. Enrichment correlated to NKG2A upregulation on CD8 sup + /sup tumor-infiltrating T lymphocytes (TIL) but not on CD4 sup + /sup TILs. CD94/NKG2A is exclusively expressed on PD-1 sup high /sup TILs while lacking intratumoral CD103 expression. We also found that the presence of CD94/NKG2A on human tumor–specific T cells impairs IL2 receptor–dependent proliferation, which affects IFNγ-mediated responses and antitumor cytotoxicity. These functionalities recover following antibody-mediated blockade i in vitro /i and i ex vivo /i . Our results suggest that enriched HLA-E:CD94/NKG2A inhibitory interaction can impair survival of PD-1 sup high /sup TILs in the tumor microenvironment. /
Location: United Kingdom of Great Britain and Northern Ireland
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 Christopher Conlon.