About the Project
Prostate cancer remains a leading cause of cancer mortality, particularly in metastatic disease where treatment options are limited. This project seeks to investigate the role of CD200, an immune checkpoint protein enriched in prostate cancer stem cells, in promoting tumour growth and immune evasion. Using genetic and pharmacological approaches, it will evaluate a novel CD200 small molecule inhibitor to determine effects on cancer stem cell function, tumour immunity and treatment response. The…
project will assess combining CD200 inhibition with conventional immunotherapy enhances anti-tumour immune responses, providing a potential new therapeutic strategy for advanced prostate cancer.
Prostate cancer (PC) is a major cause of cancer mortality worldwide, predominantly reflecting metastatic disease present at diagnosis or emerging upon androgen receptor targeted therapy (ARTT)-resistance, culminating in castration-resistant prostate cancer (mCRPC). These patients have poor prognoses (5-year survival:<30%), highlighting the urgent need for improved treatments.
CD200 is a type-I transmembrane glycoprotein functions as a novel immune checkpoint, suppressing anti-tumour immunity by inhibiting RAS/MAPK signalling and natural killer (NK) cell activity [1]. CD200 also regulates stem cell activity in multiple tissues, and enriched in cancer stem cells (CSCs, e.g., glioblastoma and melanoma) [2]. Although CD200 mutations are rare in primary/metastatic PC (<0.3%), CD200 amplification/gain correlate with worse outcome [3], suggesting a role in PC progression and immune evasion. Targeting the CD200 immune checkpoint may impair PC clonogenicity whilst overcoming tumour immune evasion and the limited efficacy of conventional immunotherapies (e.g., pembrolizumab) in PC, which exhibits low tumour mutational burden and an immunologically cold tumour microenvironment [4]. The role of CD200 in PC stem cell-mediated immunomodulation remains unclear.
Targeting CD200-CD200R signalling has been challenging, with antiCD200 antibodies showing limited clinical efficacy in haematological malignancies, despite good tolerability[5]. We developed a first-in-class CD200 small molecule inhibitor, p1019.7, which requires further preclinical evaluation before commencing early-phase clinical trials in solid cancers. Our work identified CD200+ CSCs in basal cell carcinoma (BCC) and that CD200 inhibition enhances tumour susceptibility to NK cell-mediated killing[6]. Preliminary work in PC indicates p1019.7 treatment is non-toxic/well-tolerated, reduces PC growth in-vivo, and promotes apoptosis and immune cell infiltration. Moreover, CD200 is enriched in a subset human/mouse PC stem cells [2], and p1019.7 treatment suppresses mCRPC stem cell function in-vitro (unpublished data). However, currently unknown if CD200-positive PC stem cells evade immune surveillance directly, or create an immunosuppressive niche.
We hypothesise CD200 mediates PC stem cell-mediated immune modulation and CD200 inhibition with p1019.7 will synergise with conventional immunotherapy, providing a novel therapeutic strategy to improve outcomes in PC.
Aim 1: Investigate the requirement for CD200 in PC stem cells 1.1 Perform colony forming, anchorage-independent and prostasphere assays in PC cells (C42B/PC-3/22Rv1/DU145/LNCaP) with stable CD200 knockdown (shCD200), overexpression or controls (SCRAMshRNA/empty-vector). 1.2 Determine regenerative capacity (androgen-deprivation, then testosterone supplement) and self-renewal via serial passaging using PC organoids +/- Cd200 loss. 1.3 Run RNASeq analysis on PC stem cells treated with p1019.7 or vehicle, followed by functional validation (colony forming/prostasphere assays) to identify novel therapeutic targets.
Aim 2: Define the immunomodulatory role of CD200 in PC. 2.1 Perform 2D/3D growth and immune cell-mediated killing assays using PC cell lines with manipulated CD200 expression (as Aim-1.1), cocultured with immune cells (macrophages, NK-cells or CD8+ T-cells) using HoloMonitor® time-lapse imaging; assess cytokines and immune activation. 2.2 Establish which immune cells are activated in response to p1019.7 treatment using multiplex immunofluorescence to analyse the immune infiltrate in transgenic PC tumours and patient-derived PC explants.
Aim 3: Determine the therapeutic benefit of combining CD200 inhibition and conventional immunotherapy in PC. 3.1 Perform 2D/3D immune cell-mediated killing assays of prostate cell lines (as Aim-1.1) co-cultured with immune cells (macrophages, NK-cells or CD8+ T-cells) in the presence of CD200i +/- pembrolizumab; measure cytokines and immune responses. 3.2 Test p1019.7 and pembrolizumab combination therapy in primary and metastatic transgenic/patient-derived explants with CD200i +/- pembrolizumab.
Expected outcomes:
- Define how CD200 regulates PC stem cell function and immune evasion.
- Identification of novel therapeutic targets for PC.
- Provide rationale for combining CD200 inhibitors with immunotherapy in PC.
This project offers opportunities for the student to shape the research direction and take ownership of key aspects of the work. The student will drive experimental design, data analysis, interpretation of results, and the development of follow-up studies arising from novel findings. The RNA sequencing studies and functional validation experiments provide scope to identify and prioritise new therapeutic targets, enabling the student to make an original scientific contribution. Throughout, the student will develop a broad range of highly transferable skills in cancer biology, stem cell research, immunology, and translational oncology. Technical training will include cell culture, organoid/explant ex vivo models, molecular biology techniques, immune cell killing assays, multiplex immunofluorescence, RNA sequencing analysis, and preclinical trial evaluation. The student will also gain expertise in experimental design, statistics, bioinformatics, project management, scientific writing, presentation skills, and interdisciplinary collaboration.
A full description of the project can be found on the GW4 BioMed website.
Academic criteria: Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK.
English requirements: IELTS with an overall score of 6.5 with 5.5 in all subskills, or acceptable alternative. Please see our English Language Requirements guidance for more details.
How to Apply
A list of all the projects and how to apply is available on the GW4 BioMed website. You may select up to 2 projects and submit one application per candidate only.
Please complete an application to the GW4 BioMed3 for an ‘offer of funding’. If successful, you will also need to make an application for an 'offer to study' to your chosen institution later.
Please note that we may close the application process before the stated deadline if an unprecedented number of applications are received– check the GW4 BioMed website for details and updates.
If you are shortlisted for interview, you will be notified from Tuesday, 22nd December 2026. Interviews will be held virtually on 26th and 27th January 2027. Studentships will start on 1st October 2027.
Funding Notes
These studentships are funded through GW4 BioMed3 MRC Doctoral Landscape Programme and consist of UK tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£21, 805 p.a. for 2026/27, updated each year).
Additional research training and support funding of up to £5,000 per annum is also available.
GW4 BioMed3 studentships are available to UK and International applicants
References
[1] doi:10.3389/fonc.2023.1088038
[2] doi:10.1016/j.bbrc.2007.10.067
[3] doi:10.1158/2159-8290.CD-12-0095
[4] doi:10.1186/s12885-020-07058-y
[5] doi:10.1186/s40425-019-0710-1
[6] doi:10.1172/JCI150750
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