Targeting tumour-specific T cell dysregulation to intercept lung cancer

Primary supervisor: James Reading, UCL

Secondary supervisor: Timothy Tree, King’s College London

Project

Non-small cell lung cancer (NSCLC) is the leading cause of cancer related death worldwide. Late-stage NSCLC is mostly lethal, engendering an ongoing clinical effort to both detect and intervene earlier in the disease process. Unfolding low-dose CT (LDCT) screening programmes targeting high-risk populations are helping to achieve this and transform outcomes by detecting early-stage lung cancers. Interestingly, these screens are also identifying premalignant lesions that progress to NSCLC; creating an unprecedented opportunity to ‘intercept’ disease and thus prevent or delay invasion. However, clinical protocols for NSCLC interception remain underdeveloped, since we lack an understanding of the targetable pathways driving early tumorigenesis.

We and others have discovered that immune regulation occurs during pre-malignant progression and can be tracked and targeted to intercept NSCLC in vivo [1,2]. This is patterned by disruption to co-stimulation and antigen presentation and an early cross-tissue burst of potently suppressive effector Tregs [Reading lab, Nature in press 2026 – 3]. A greater understanding of how the immune system, and particularly the CD8 T cell response, is dysregulated at this stage of disease may inform strategies to intercept cancer.

Recent work from our lab has for the first time, detected neoantigen-reactive T cells in patients with premalignant lesions, years before invasive disease occurs. Our observations suggest that this response is corrupted via extrinsic (Treg), intrinsic (early exhaustion within lesions) and systemic (loss in the blood, suppression in the lymph node) dysregulation, which defines future NSCLC risk. These pathways are also evident in mouse models of NSCLC progression [4,5]. Targeting dysregulation of the preinvasive CD8 T cell response via vaccination and precision checkpoint inhibition could offer a novel NSCLC interception strategy.

This project will test the hypothesis that targeting preinvasive neoantigen reactive T cell dysregulation can intercept NSCLC, comprising three aims

1. Identify Tneo cells in the blood, LN and pre-invasive lesions of patients progressing to NSCLC in CT screening.
2. Use T cell reactivity aware multi-omics data to define targetable axes of Tneo regulation for interception.
3. Utilise cutting edge human and/or mouse models to functionally reprogramme this response via mAbs, neoantigen vaccines and next-gen therapeutics.

You will have extensive support from a large international multi-disciplinary team, broad translational, computational and experimental infrastructure, and globally unique pre-cancer data sets and cohorts. You will benefit from access to a first of its kind clinically active lung cancer vaccine and rare samples from our ongoing clinical trial.

Summary:

This project will identify and validate pathways of preinvasive immune dysfunction across the blood, tissue and tdLN with the aim to test targets which can intercept and prevent the formation of invasive lung cancer.

Candidate background

The candidate will have an undergraduate degree relating to cancer biology or immunology and be willing to carry out both wet and dry lab research as part of a dynamic multi-disciplinary team. Ideally, the candidate will have experience in cell culture, flow cytometry and R/Python.

Potential placements

1. Nik Joshi, Yale (US)
2. Febe van Maldegem, VuMC (NL)
3. TBC

References

1. Pennycuick, A. et al. Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer. Cancer Discov. 10, 1489–1499 (2020).
2. Mascaux, C. et al. Immune evasion before tumour invasion in early lung squamous carcinogenesis. Nature 571, 570–575 (2019)
3. Gamble et al . A Preinvasive Treg Axis for Lung Cancer Interception, Nature (2026) – issue pending.
4. Schenkel, J. M. et al. Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1+ CD8+ T cells in tumor-draining lymph nodes. Immunity 54, 2338-2353.e6 (2021).
5. Connolly, K. A. et al. A reservoir of stem-like CD8+ T cells in the tumor-draining lymph node preserves the ongoing antitumor immune response. Sci. Immunol. 6, eabg7836 (2021).