Remodelling the Metastatic Niche: LRG1 as a Gateway to Effective Immunotherapy in Group 3 Medulloblastoma

Project

Among the molecular subtypes of medulloblastoma (MB), Group 3 carries the worst prognosis, characterised by a high rate of leptomeningeal spread, treatment resistance, and poor outcomes. Little is understood about how disseminated tumour cells persist and evade immune detection within the cerebrospinal fluid (CSF) and leptomeningeal space, posing a significant obstacle to effective immunotherapy. While chimeric antigen receptor (CAR) T-cell immunotherapies show early promise, their efficacy against metastatic disease remains limited, suggesting disseminated tumour cells establish a profoundly immunosuppressive microenvironment driving both spread and therapeutic resistance.

Using our novel MMB mouse model and complementary human tumour datasets, we identified Leucine-rich alpha-2 glycoprotein-1 (LRG1) as a promising therapeutic target enriched in MMB. LRG1 is a secreted regulator of TGF-β signalling, that facilitates angiogenesis, immune suppression and metastatic spread of cancer. Its secreted nature makes it a particularly attractive target, enabling therapeutic interception without the need for intracellular access.

Hypothesis: MMB cells exploit LRG1-dependent signalling through modulation of TGF-β to evade anti-tumour immunity, promote leptomeningeal dissemination, and reduce CART-cell efficacy.

Aim-1. Define how LRG1 shapes the TME of MMB. LRG1 upregulation in MMB is associated with an immunosuppressive TME, yet the immune populations and cell states it governs within the leptomeningeal compartment remain undefined. Using single-cell RNA-sequencing, spatial transcriptomics, and multiplex imaging across paired primary and metastatic lesions, we will characterise LRG1 expression, quantify immune infiltrates in LRG1-high versus LRG1-low metastases, and determine whether LRG1 is linked to discrete metastatic cell states and a consistent immunosuppressive leptomeningeal niche, with particular focus on myeloid recruitment and T-cell dysfunction.

Aim-2. Determine the functional role of LRG1 in dissemination. While correlative data implicate LRG1 in metastatic progression, its functional contribution to immune evasion and dissemination in MMB remains unestablished. Using genetically engineered MMB mouse models, LRG1 gain- and loss-of-function studies will assess metastatic burden, immune infiltration, and anti-tumour responses.. Given LRG1’s role in destabilising tumour vasculature, we will examine whether its loss reduces vascular permeability and cancer cell escape, and whether tumour-derived LRG1 reprogrammes myeloid populations toward immunosuppressive states to suppress cytotoxic T-cell activity and facilitate dissemination.

Aim-3. Test whether targeting LRG1 enhances CAR T-cell therapy against MMB. The limited efficacy of CAR T-cell therapy against metastatic disease likely reflects the immunosuppressive niche in which LRG1 may play a central role. Using immune-competent and MMB models, we will compare the therapeutic effects of CAR-T cells in this setting alongside armouring approaches to neutralise LRG1 signaling that have been developed in our laboratories. Endpoints will include CAR T-cell trafficking and persistence within the leptomeningeal compartment, TME remodelling, metastatic burden, and survival, directly testing whether LRG1 blockade can remodel the immunosuppressive niche and restore CAR T-cell efficacy in the metastatic setting.

Candidate background

A background in cancer biology, immunology and/or neuroscience is required. An interest in tumour-host interactions, metastatic disease, and immunotherapy is highly desirable.

The project combines in vivo modelling, molecular and cellular biology, single-cell genomics, and immunotherapy development. Previous research experience in one or more of these areas would be beneficial but is not required. The successful candidate must be keen to develop expertise in translational cancer research and the development of new therapies.

Potential placements

1. James Arnold, Comprehensive Cancer Centre, King’s College London
2. John Anderson, Institute of Child Health, UCL
3. Amanda Fitzpatrick, Comprehensive Cancer Centre, King’s College London

References

1. O’Connor, M.N. et al., Med. 2, 1231-1252 (2021)
2. Donovan, L. K. et al. Nature Medicine 26, 720-731 (2020).
3. Draper, B.O. et al., Neuro-oncology (2026)
4. Opzoomer. et al., Sci Adv. 7. (2021)
5. Morrissy, A. S. et al. Nature 529, 351–357 (2016).