Project ID CM-HD2024_45


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Basic & Medical Biosciences, Centre for Gene Therapy & Regenerative MedicineWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Peter Gorer Department of ImmunobiologyWebsite

Characterising the Tumour-Associated Regulatory T cell (Treg)-Stem Cell Niche

Tumour-infiltrating Tregs (TI-Tregs) and stromal cells, including epithelial stem cells (SCs), are key components of the tumour-microenvironment and play important roles in cancer progression, yet their relationships and interdependencies remain poorly understood. To elucidate TI-Treg association with diverse tumour-supporting accessory cell types, this project will explore immediate early changes in their single-cell transcriptomes and intratumoural localisation in i) mouse cancer models (e.g. B16-F10 melanoma) where Tregs are genetically deleted, and ii) primary human tumour sample analysis.

Year 1/2. Identifying Treg SC niches. a) Identify the abundance and activation of Tregs and accessory cell types in tumour tissues by flow cytometry and imaging using reporter mice for Foxp3 (transcription factor to identify Tregs) b) Conditional deletion of Tregs in Foxp3-DTR mice during early tumour development to assess impact on tumour cell populations using RNA sequencing and multi-labelled tissue array (TAs) based in situ transcriptomic and proteomics.

Year 2/3. Interrogate Treg function via manipulation of the niche. We hypothesise that deletion of Tregs during early cancer development will impact specific populations of stromal and/or epithelial SCs. We will then assess the impact on tumour-progression and metastasis in the cancer model.

Year 3/4. Characterizing tumour SC-Treg dialogue. Single-cell RNA sequencing will be used to unravel the molecular basis of the tumour SC-Treg dialogue in tumours, through identification of pairs of ligands/receptors that are expressed by tumour cells and Tregs. The candidate molecules in the niche will be tested using using Cre/lox mediated conditional gene-targeting and validation in human tumour samples using TAs and flow cytometry.

The Ali lab has specific expertise in tissue immune cell-stem cell interactions and has established genetic tools to study Tregs and tissue stromal cells in cancer models. The Lombardi lab has over 30 years of experience with studying the mechanisms used by both human and mouse TI-Tregs.

Representative Publications

Regulatory T cells in skin facilitate epithelial stem cell differentiation. Ali N,.…Nestle FO, Paus R, Cotsarelis G, Abbas AK, Rosenblum MD. 2017 Cell DOI: 10.1016/j.cell.2017.05.002 Treg-Cell Control of a CXCL5-IL-17 Inflammatory Axis Promotes Hair-Follicle-Stem-Cell Differentiation During Skin-Barrier Repair Mathur A,….Abbas AK, Ali N, & Rosenblum MD. 2019 Immunity DOI: 10.1016/j.immuni.2019.02.013 Tissue Regulatory T cells Lui P, Cho I, Ali N. 2020. Immunology DOI: 10.1111/imm.13208.
An atlas of human regulatory T helper-like cells reveals features of TH2-like Tregs that support a tumorigenic environment • Halim L. Romano M., McGregory R., Lechler R.I., Nova-Lamperti E, Lombardi G. 2017 Cell Reports. • DOI: 10.1016/j.celrep.2017.06.079 Effector and Regulatory CD4+ T helper lineages in cancer Nova-Lamperti E, Fraga M, Romano M, Lombardi G. 2018 Journal of Cancer Treatment and Diagnosis DOI:10.29245/2578-2967/2018/1.1119