Tumour Immunology
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
We are pursuing several different lines of investigation with the common goal of improving treatment strategies for cancer. The ability of cancer cells to avoid destruction by the immune system means that as yet there is no effective treatment. We know that in several different types of cancer there are increased numbers of cells called myeloid suppressor cells (MDSC) that suppress the immune system, and therefore allow cancer cells to continue to grow and divide. We also know that another kind of immune cells - invariant natural killer T (iNKT) cells –monitor malignant cells and decrease the numbers of circulating MDSCs in melanoma patients, thus restoring the immune response to cancer cells. These iNKT cells are very important because they form a “bridge” between the part of the immune system that recognises foreign proteins and the part that destroys abnormal cells. By studying the behaviour of iNKT cells we aim to find ways of increasing their activity in a controlled way, and use them to “jump-start” immune responses to tumour cells. Our clinical trial program is presently translating preclinical findings into phase I and II clinical trials of cancer vaccine candidates.
Technical Summary
Goals To develop vaccination strategies to enhance tumour specific T cell responses. By bridging the innate and adaptive arms of the immune system invariant NKT (iNKT) cells can be harnessed to jump-start antigen-specific immune responses. Stimulation of iNKT cells in vivo with the specific synthetic ligands results in significantly enhanced immune responses to protein-based vaccines. Further, activation of human dendritic cells (DC) by toll-like receptor (TLR) agonists modulates the lipid biosynthetic pathway, resulting in enhanced recognition of CD1d associated lipids by iNKT cells. Thus, iNKT cells significantly influence the efficacy of immune responses to soluble antigen by modulating DC function, supporting the concept that there is substantial immunostimulatory power in the integration of iNKT cell- and TLR-mediated signals to dendritic cells. We have characterized by structural (1), kinetic (2), and functional (2,3) studies a novel family of NKT cell agonists (4), and more recently shown that iNKT cells modulate the suppressive activity of neutrophils (5). A large proportion of melanoma cells produces the major acute-phase reactant serum amyloid A-1 (SAA-1), one of the first and most abundant proteins secreted during the physiological response to infection and injury. By binding to formyl-peptide receptor 2 expressed by neutrophils, SAA induces them to secrete IL-10 which suppresses the T cell response. CD1d- and CD40- dependent interaction of neutrophils with iNKT cells ameliorates this suppressive activity indicating a pivotal role anti-tumour responses (5). Tumours also evade immune responses by depleting tryptophan via the tryptophan catabolizing enzyme indoleamine 2,3 dioxygenase (IDO). Such depletion induces regulatory T cells and inhibits effector T cells. Local tryptophan depletion is overcome by IDO positive tumour cells by the expression of a novel amino acid transporter distinct from system L (6) - this increases tryptophan entry into IDO positive tumours, depleting the microenvironment further. This additional tryptophan transporter could be the key to pharmacological inhibition of IDO mediated tumour escape (6). The ability to direct homing of antigen specific T cells to specific tumour tissue is crucial to anti-tumour strategies. We have extended the notion that production of retinoic acid (RA) by dendritic cells (DCs) is critical for development of gut-tropic immune responses by demonstrating that Prostaglandin E2 blocks expression of retinal dehydrogenases (RALDH) - enzymes responsible for converting vitamin A into RA - abrogating the ability to induce CCR9 expression upon T cell priming (7). Future research plans Future work aims to characterize further strategies to enhance immune responses and to modify the tumour microenvironment, with emphasis on: (a) the role of iNKT cells in bridging the adaptive and innate immune responses; (b) the plasticity of myeloid cells in regulating tumour specific immune responses; (c) the role of tryptophan degrading enzymes in upregulating higher affinity tryptophan transporters; and (d) vaccine clinical trials in melanoma patients. References: (1) Koch et al. 2005 Nature Immunol 6: 819 (2) McCarthy et al 2007 J Exp Med 204: 1131 (3) Salio et al 2007 Proc Natl Acad Sci 104:20490 (4) Silk et al 2008 J Immunol 180: 6452 (5) De Santo et al 2010 Nature Immunol 11: 1039 (6) Silk et al 2011 J Immunol 187: 1617 (7) Stock et al 2011 J Exp Med 208: 761.
Organisations
- University of Oxford (Lead Research Organisation)
- UNIVERSITY OF OXFORD (Collaboration)
- Cancer Research UK (Collaboration)
- HARVARD UNIVERSITY (Collaboration)
- HUMABs Biomed, Bellinzona,Switzerland (Collaboration)
- PUBLIC HEALTH ENGLAND (Collaboration)
- Scripps Research Institute (Collaboration)
- UCB Pharma (Collaboration)
- National Institute for Biological Standards and Control (NIBSC) (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- Medical Research Council (MRC) (Collaboration)
People |
ORCID iD |
Vincenzo Cerundolo (Principal Investigator) |
Publications
Gibani MM
(2019)
The Impact of Vaccination and Prior Exposure on Stool Shedding of Salmonella Typhi and Salmonella Paratyphi in 6 Controlled Human Infection Studies.
in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Jin C
(2019)
Treatment responses to Azithromycin and Ciprofloxacin in uncomplicated Salmonella Typhi infection: A comparison of Clinical and Microbiological Data from a Controlled Human Infection Model.
in PLoS neglected tropical diseases
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00008/1 | 31/03/2017 | 30/03/2023 | £2,738,000 | ||
MC_UU_00008/2 | Transfer | MC_UU_00008/1 | 31/03/2017 | 30/03/2023 | £1,821,000 |
MC_UU_00008/3 | Transfer | MC_UU_00008/2 | 31/03/2017 | 30/03/2023 | £2,257,000 |
MC_UU_00008/4 | Transfer | MC_UU_00008/3 | 31/03/2017 | 30/03/2023 | £1,459,000 |
MC_UU_00008/5 | Transfer | MC_UU_00008/4 | 31/03/2017 | 30/03/2023 | £1,346,000 |
MC_UU_00008/6 | Transfer | MC_UU_00008/5 | 31/03/2017 | 30/03/2023 | £1,660,000 |
MC_UU_00008/7 | Transfer | MC_UU_00008/6 | 31/03/2017 | 30/03/2023 | £401,000 |
MC_UU_00008/8 | Transfer | MC_UU_00008/7 | 31/03/2017 | 31/03/2024 | £2,876,000 |
MC_UU_00008/9 | Transfer | MC_UU_00008/8 | 31/03/2017 | 30/03/2023 | £2,568,000 |
MC_UU_00008/10 | Transfer | MC_UU_00008/9 | 31/03/2017 | 30/03/2023 | £2,060,000 |
MC_UU_00008/11 | Transfer | MC_UU_00008/10 | 31/03/2017 | 30/03/2023 | £1,477,000 |
Description | CRUK-MedImmune Alliance |
Amount | £74,000 (GBP) |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2015 |
End | 08/2017 |
Description | European Commission Horizon 2020 |
Amount | £672,000 (GBP) |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 03/2016 |
End | 03/2021 |
Description | KKLF Equipment Grant |
Amount | £468,000 (GBP) |
Funding ID | KKL1057 |
Organisation | The Kay Kendall Leukaemia Fund |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2016 |
End | 03/2017 |
Description | MRC Capital Prioritisation Equipment Bid |
Amount | £120,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2017 |
End | 02/2018 |
Description | Marie Curie European Fellowship |
Amount | £135,000 (GBP) |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 09/2015 |
End | 09/2017 |
Description | STREAM - Strategies for Excellence in Immuno-Oncology |
Amount | £97,000 (GBP) |
Funding ID | 692180 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 12/2015 |
Description | UK Vaccine Network |
Amount | £2,046,000 (GBP) |
Organisation | Department of Health (DH) |
Sector | Public |
Country | United Kingdom |
Start | 08/2016 |
End | 08/2019 |
Description | B cell biology and NKT cells |
Organisation | Cancer Research UK |
Department | Cancer Research UK London Research Institute (LRI) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Collaborative work on the interaction of the innate and adaptive immune responses has led to two publications. We study the role of NKT cells in this interaction. |
Collaborator Contribution | Collaborative work on the interaction of the innate and adaptive immune responses has led to two publications. The collaborator studies the role of B cells in this interaction. |
Impact | Publications: 20228797 18550831 |
Start Year | 2007 |
Description | Collaboration with HUMABs, Switzerland |
Organisation | HUMABs Biomed, Bellinzona,Switzerland |
Country | Switzerland |
Sector | Private |
PI Contribution | Isolation of a cocktail of neutralizing antibodies from vaccinees to compare with the ZMapp cocktail derived from murine antibodies |
Collaborator Contribution | Collaborative project and supply of antibodies |
Impact | No published outcome yet |
Start Year | 2016 |
Description | Collaboration with Harvard University |
Organisation | Harvard University |
Department | Harvard Medical School |
Country | United States |
Sector | Academic/University |
PI Contribution | Analysis of CD1 restricted Salmonella-specific T cell responses |
Collaborator Contribution | Collaborative project |
Impact | Publications of papers in peer-reviewed journals. |
Start Year | 2013 |
Description | Collaboration with NIBSC |
Organisation | National Institute for Biological Standards and Control (NIBSC) |
Country | United Kingdom |
PI Contribution | Isolation of a cocktail of neutralizing antibodies from vaccinees to compare with the ZMapp cocktail derived from murine antibodies |
Collaborator Contribution | Collaborative project |
Impact | No published outcome yet |
Start Year | 2016 |
Description | Collaboration with Professor Sarah Teichmann |
Organisation | The Wellcome Trust Sanger Institute |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | Single cell RNAseq analysis of CD4 T cell responses to Salmonella Typhi and Paratyphi |
Collaborator Contribution | Collaborative project |
Impact | No published outcome yet |
Start Year | 2015 |
Description | Collaboration with Professor Yvonne Jones' Group |
Organisation | University of Oxford |
Department | Division of Structural Biology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are developing a collaboration on the role of semaphorins in hampering T cell responses |
Collaborator Contribution | Collaborative project |
Impact | No published outcomes yet |
Start Year | 2016 |
Description | Collaboration with Public Health England |
Organisation | Public Health England |
Country | United Kingdom |
Sector | Public |
PI Contribution | Isolation of a cocktail of neutralizing antibodies from vaccinees to compare with the ZMapp cocktail derived from murine antibodies |
Collaborator Contribution | Collaborative project |
Impact | No published outcome yet |
Start Year | 2016 |
Description | Collaboration with UCB Celltech |
Organisation | UCB Pharma |
Country | United Kingdom |
Sector | Private |
PI Contribution | Isolation of a cocktail of neutralizing antibodies from vaccinees to compare with the ZMapp cocktail derived from murine antibodies |
Collaborator Contribution | Collaborative project |
Impact | No published outcome yet |
Start Year | 2016 |
Description | Collaboration with the MRC Molecular Haematology Unit |
Organisation | Medical Research Council (MRC) |
Department | MRC Molecular Haematology Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are studying how nutritional stress alters the transcriptomic profile of AML blasts and T lymphocytes |
Collaborator Contribution | Collaborative project |
Impact | No published outcomes yet |
Start Year | 2016 |
Description | Collaboration with the Oxford Vaccine Group |
Organisation | University of Oxford |
Department | Oxford Vaccine Group |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | In the context of the MRC Experimental Medicine Challenge Grant, my group has set up a close collaboration with the Oxford Vaccine Group directed by Professor Andrew Pollard. |
Collaborator Contribution | As a joint collaboration, we are investigating disease mechanisms in enteric fever to characterise innate and adaptive immunity in mucosa and blood in controlled human infection models |
Impact | Collaboration still ongoing |
Start Year | 2014 |
Description | Collaboration with the Viral Hemorrhagic Fever Immunotherapeutic Consortium |
Organisation | Scripps Research Institute |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | Isolation of a cocktail of neutralizing antibodies from vaccinees to compare with the ZMapp cocktail derived from murine antibodies |
Collaborator Contribution | Collaborative project and supply of antibodies |
Impact | No published outcome yet |
Start Year | 2016 |
Company Name | iOx Therapeutics |
Description | The company is centred around development of the use of NKT cell agonists in cancer patients. The close affiliation with the Ludwig Institute will provide access to GMP grade recombinant tumour antigens, which will be used in combination with proprietary GMP grade NKT cell agonists in the clinic. We have recently secured funding from the EC (Horizon 2020), with iOx being listed as a co-applicant. |
Year Established | 2015 |
Impact | None yet |
Description | Article in WIMM Blog on invariant natural killer T cells |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | An article entitled "Lights, Camera, Immuno-action!" on WIMM Blog presenting research on invariant natural killer T cells, and the role they may be able to play in the fight against cancer. |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.imm.ox.ac.uk/wimm-blog-2 |
Description | Developing resources for teachers to use in classroom |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Working as part of team developing resources for teachers to help them enrich their curriculum with hands-on classroom activities, an existing activity that illustrates blood group compatibility to students was adapted and teaching materials for teachers were developed to conduct the experiment with students in classroom. This included the design of worksheets for the students and a detailed lesson plan for the teachers as well as introductory materials. A 3-minute animation explaining the immunological concepts underlying antibody-mediated immunity was written and produced. |
Year(s) Of Engagement Activity | 2017,2018 |
Description | Flow Cytometry Talk for In2Science work experience programme |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | The aim was to introduce participants of the WIMM work experience programme to the basic concepts of flow cytometry; audience: high school age participants of the WIMM work experience programme |
Year(s) Of Engagement Activity | 2018 |
Description | Hands on activities at the Oxford Museum of Natural History |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | "The Blood Factory" - hands on activities about blood at the Museum of Natural History for secondary school students, adults etc. |
Year(s) Of Engagement Activity | 2017 |
Description | Hands-on activities during Royal Society Summer Exhibition, London |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Hands-on activities, including virtual reality tour of DNA, during Royal Society Summer Science Exhibition, Royal Society London. |
Year(s) Of Engagement Activity | 2017 |
Description | Hosting of an A-level student |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Last year we hosted Jasmine Godden, July 16-19 2018. She was a 6th former student at Cheney and was interested in Cancer Immunotherapy. She shadowed members of the Lab and discussed with them their research, then she wrote an essay on Cancer Immunotherapy in Melanoma. She got an A* for this work, as part of her EPQ. She now intends to apply for medical school. |
Year(s) Of Engagement Activity | 2018 |
Description | Hosting of severl A-level Work Experience students |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | The Group hosted five A-level students from local schools for a period of Work Experience. Two of the students subsequently decided to go on to study medicine. |
Year(s) Of Engagement Activity | 2019 |
Description | MRC Festival of Medical Research |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | We set up and organised the "Cancer Immunotherpy Stand" in the context of the yearly MRC Festival of Medical Research |
Year(s) Of Engagement Activity | 2019 |
Description | MRC Festival of Medical Research |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Participation in a co-organised event set up in a series of regional supermarkets to raise awareness of the research and science carried out by the MRC |
Year(s) Of Engagement Activity | 2018 |
Description | MRC Festival of Science |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | The aim was to inform and engage with the public about gene editing techniques; audience: passers-by in the Newbury pedestrian zone |
Year(s) Of Engagement Activity | 2018 |
Description | Oxford Hands-On Science school visit |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | The aim was to share enthusiasm for science with school pupils by taking hands-on science activities into classrooms; audience: local school children |
Year(s) Of Engagement Activity | 2018 |
Description | Oxford Science and Ideas Festival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Our group set up a Cancer Immunotherapy stand at the Oxford Science and Ideas festival |
Year(s) Of Engagement Activity | 2019 |
Description | Participation in Summer Roadshow - part of Oxford Hands-On Science (OXHOS) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Participation in 2017 Summer Road Show by Oxford Hands-On Science - participating and help in organising activities in schools in and around Oxford in June and also a week of activities in various schools on the Isle of Wight in July. |
Year(s) Of Engagement Activity | 2017 |
URL | http://oxhos.org/PDFs/OxHOS_Roadshow_Report_Summer_2017.pdf |
Description | Secondary school student one day visit to the lab |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Secondary school student visited research lab for one day and shadowed a Post Doc observing lab work and experiments. |
Year(s) Of Engagement Activity | 2017 |
Description | Secondary school student visited research lab for work experience and one day shadowing. |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | A secondary school student visited immunology research lab to get work experience and observe scientists in their daily work. |
Year(s) Of Engagement Activity | 2017 |
Description | Teacher Training Evening |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | The aim was to equip teachers to use teaching resources on antibodies and microscopy developed by Eggeling and Cerundolo labs to enhance science curriculum with hands-on activities |
Year(s) Of Engagement Activity | 2018 |
Description | Town and Gown Marathon |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other audiences |
Results and Impact | Participation as the MRC Human Immunology team in the annual sponsored charity Town and Gown marathon |
Year(s) Of Engagement Activity | 2018 |
Description | Volunteering in Settlers Exhibition, Oxford Museum of Natural History |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | An Exhibition to raise awareness into DNA and VR |
Year(s) Of Engagement Activity | 2018 |