Dissecting Immune-Stromal Crosstalk to Define Prognostic Endotypes in NSCLC

Precision Medicine Project - Dissecting Immune-Stromal Crosstalk to Define Prognostic Endotypes in NSCLC

Supervisor(s): Prof Ahsan Akram, Dr Florent Petitprez, Prof Prakash Ramachandran & Prof John Le Quesne (University of Glasgow)
Centre/Institute: Centre for Inflammation Research, Institute of Regeneration and Repair

Background

Non-small cell lung cancer (NSCLC) is a biologically and clinically heterogeneous disease, representing the majority of lung cancer diagnoses and the leading cause of cancer death worldwide. While immune checkpoint blockade has improved outcomes for some patients, a significant proportion derive little to no benefit from immunotherapy. Stratifying patients for appropriate treatment, based on biologically meaningful disease endotypes, remains an urgent challenge. This proposal aims to investigate this by integrating multidimensional clinical and molecular data to identify diagnostically, prognostically, and mechanistically relevant subgroups. 

Our work has identified prognostic associations between specific immune and stromal populations in NSCLC, including T cells, B cells, and cancer-associated fibroblasts (CAFs). However, it is clear that these cell types do not act in isolation, but rather engage in complex, context-dependent crosstalk shaped by the surrounding tumour microenvironment (TME). In particular, the canonical adenosine pathway appears to be a key modulator of this interaction, promoting local immune suppression and altering cellular positioning and function. Through a series of studies, we have demonstrated the prognostic and mechanistic relevance of this tri-directional cellular interplay. Mathieson et al. showed that CAFs expressing fibroblast activation protein and podoplanin are linked to poor clinical outcomes, likely through mechanisms involving immune exclusion and extracellular matrix remodelling. O’Connor et al. further demonstrated that CAFs can drive CXCL13 production in activated T cells via TGF-beta signalling, a pathway that influences B cell recruitment and tertiary lymphoid structure formation in a context-dependent manner. Additionally, Koppensteiner et al. found that the spatial location of CD39-positive T cells within tumours predicts differential outcomes, with their presence in tumour nests or stromal regions carrying distinct prognostic significance.  Together, these findings suggest the existence of immunologically and spatially defined NSCLC endotypes, which reflect not just the abundance of individual cell types, but the nature of their interactions. This project seeks to map and understand this cross-talk in situ, with the goal of defining novel prognostic endotypes that can guide treatment decisions and the development of novel combination strategies. The multiplex panel is being optimised for each antibody component, ensuring the student will have minimal further optimisation prior to undertaking the imaging on the TMA. 

Aims

This PhD project will investigate multi-directional immune-stromal crosstalk in NSCLC to define spatial and functional signatures associated with poor prognosis and therapy resistance. The specific aims are:

  1. To image a high-dimensional 60-marker immunofluorescence (IFF) panel, for profiling immune and stromal phenotypes within a clinically annotated NSCLC tissue microarray from 350 patients
  2. To perform computational and spatial analyses of T cell, B cell, and CAF cross-talk, including their relationship with adenosine pathway activation, tumour stage, radiological features, and response to therapy
  3. To integrate the previous analysis with open access large-scale single-cell RNA-sequencing data to characterise populations of interest at the full transcriptome resolution.
  4. To extend observation of clinical relevance of particular cell subsets by performing deconvolution of open source clinically characterised cohorts with bulk RNA-sequencing to determine associations with patients survival and response to therapeutic modalities, in particular immunotherapies.
  5. To conduct focused mechanistic experiments using fresh human NSCLC tissue, including co-culture assays, tumour organoids, and precision-cut lung slices, to validate key pathways and cellular interactions identified in tissue studies

Training outcomes

The student will receive multidisciplinary training in both experimental and computational methods. This will include expertise in tissue handling, multiplexed imaging, advanced microscopy, co-culture and ex vivo lung models, and mechanistic immunology. In parallel, the student will be trained in high-dimensional image analysis, spatial imaging analysis and statistics, and clinical data integration. This project will also foster development in key areas including critical thinking, independent scientific inquiry, ethical data stewardship, and communication of complex scientific findings to both specialist and non-specialist audiences.

Working within a supportive and collaborative research environment, the student will engage with a wide range of translational researchers, clinicians, and data scientists, gaining a well-rounded education in the application of spatial biology and precision oncology to real-world clinical challenges.

References 

  1. Mathieson, L. et al. (2020). Cancer-associated fibroblasts expressing fibroblast activation protein and podoplanin in non-small cell lung cancer predict poor clinical outcome. British Journal of Cancer.
  2. O’Connor, R. A. et al. (2023). Cancer-associated fibroblasts drive CXCL13 production in activated T cells via TGF-beta. Frontiers in Immunology.
  3. Koppensteiner, L. et al. (2022). Location of CD39+ T cell subpopulations within tumors predicts differential outcomes in non-small cell lung cancer. Journal for ImmunoTherapy of Cancer.
  4. Hanahan, D., and Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674.

Apply Now

Click here to Apply Now

  • The deadline for 26/27 applications is Monday 12th January 2026
  • Applicants must apply to a specific project. Please ensure you include details of the project on the Recruitment Form below, which you must submit to the research proposal section of your EUCLID application.
  • Please ensure you upload as many of the requested documents as possible, including a CV, at the time of submitting your EUCLID application.  

Q&A Sessions

Supervisor(s) of each project will be holding a 30 minute Q&A session in the first two weeks of December. 

If you have any questions regarding this project, you are invited to attend the session on TBC via Microsoft Teams. Click here to join the session.

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