Immune evasion in prostate cancer version 1.0
Research type
Research Study
Full title
Immune Evasion in Prostate Cancer
IRAS ID
258002
Contact name
Michael Brown
Contact email
Sponsor organisation
University of Manchester
Clinicaltrials.gov Identifier
19_HTS04_10, Internal HTA
Duration of Study in the UK
2 years, 4 months, 30 days
Research summary
Research Summary
Prostate cancer (PCa) is the second most common cancer in men worldwide and has a predilection to spread to the bone marrow stroma (BMS) or lymph nodes (LN), with spread to both sites correlating with shortest overall survival period. The reasons for this site specificity and natural history are unclear. Recent analysis of publically available prostate cancer genetic databases by our group has highlighted genetic alterations which may affect the way in which tumour cells appear to the immune system, in particular the MHC-I surface molecule through which the cell presents targets to the immune system. These alterations, and where they occur, have the potential to enable the tumour to evade the systemic immune system and allow the distant spread of the disease.Here we will characterise the immune micro-environments associated with prostate cancer progression in an archival cohort of men who underwent a radical prostatectomy with extended lymph node dissection for PCa. Using archival pathological specimens stored in paraffin embedded blocks, we will assess the MHC-I status of the metastatic prostate lesions lymph nodes and correlate with long term clinical outcome. The immune microenvironment within the metastatic lymph nodes will be correlated with MHC-I status and clinical outcome to determine the role of target presentation within lymph node metastases on systemic immune evasion.
Genetic characterisation of the antigen presentation pathway of the lymph node metastasis will also provide genetic biomarkers which will enable the pairing of the metastasis with its originating primary lesion. This will enable targeted characterisation of the immune microenvironment using a multi-marker approach, of the aggressive primary lesion. Along with providing insight into the role/inactivation of the immune system in PCa progression, this will provide novel biomarkers, which can be used at point of initial prostate biopsy, indicative of risk of wider systemic spread.
Summary of Results
The aim of this project was to determine if the spread of prostate cancer to a local lymph node, which contain potentially cancer fighting immune cells, affects the immune environment of the primary tumour within the prostate and thereby enabling the prostate cancer to progress.
All samples were acquired from the Manchester Cancer Research Centre (MCRC) Biobank under their biobank ethics and protocols. In total we sampled paired primary prostate cancer lesion and associated lymph nodes from 28 archival prostate cancer patients with or without local lymph node metastases stored within the MCRC biobank. These samples were used to construct prostate cancer macro-arrays (TMA). This allows all the patients to be put together into a single block allowing for all the patients to be stained and analysed simultaneously, and thereby reducing the potential variation in staining intensity associated with staining each patient sample individually.
The TMAs have been stained and imaged with 3 panels of markers to label the immune cell types and immune signalling pathways present. We are currently in the final stages of analysing the panels at a single cell level to generate maps displaying the type and number of immune cells (T cells, professional antigen presenting cells (Macrophage/Dendritic Cells), Natural Killer (NK) cells) and the immune signalling pathways (PDL-1, inflammatory) present within each patients’ samples along with the spatial location of each immune cell deposit in correlation with the prostate tumour. Once these maps are complete, we will then compare the immune cell profile of the primary prostate tumour with their associated lymph node to determine the effect of prostate cancer within the local lymph node on the immune environment of the primary prostate cancer. Generating spatial maps of the immune system within the prostate and associated lymph nodes is complex and we anticipate completion of the study within the next 12 months, with subsequent publication in a peer reviewed journal and presentation at scientific meetings. Future work will be to determine the interplay between the different immune cell types which will provide an insight into the immune dysregulation enabling the spread of prostate cancer to distant sites such as the bone.
This work is part of a clinical PhD studentship within the Genito Urinary Cancer Research group, University of Manchester, funded by the Salford Royal Urology Research Fund.REC name
North West - Greater Manchester Central Research Ethics Committee
REC reference
20/NW/0280
Date of REC Opinion
13 Jul 2020
REC opinion
Further Information Favourable Opinion