PhD Grant Application: Interactions between IL-18-armoured NKG2D CAR T Cells and the Triple Negative Breast Cancer Microenvironment (360G-Wellcome-336993_Z_25_Z)

Triple-negative breast cancer (TNBC) has poor prognosis due to few treatment options. CAR T-cell therapies, which redirect T cells to target tumours, show efficacy in immunodeficient mouse models of TNBC, but clinical benefits remain limited. A major barrier to efficacy is the immunosuppressive tumour microenvironment (TME). This PhD will investigate how murine NKG2D-based CAR (mLEU011) T cells remodel the TNBC TME in immunocompetent mice. I hypothesise that mLEU011 will shift the TME from immunosuppressive to immunoreactive by targeting NKG2D ligand-expressing immunosuppressive cells, and by activating endogenous immunity via epitope spreading. I predict that armouring mLEU011 CAR T cells with the pro-inflammatory cytokine IL-18 will enhance these immunoreactivating effects. To test this, I will generate IL-18-armoured mLEU011 CAR T cells, validate their function in vitro, and assess safety in vivo. In parallel, I will establish a syngeneic mouse model of TNBC to evaluate CAR T-cell efficacy and profile TME changes and host immune activation. Changes in the TME will be analysed using flow cytometry, multiplex immunohistochemistry (mIHC), and spatial transcriptomics. This project will provide mechanistic insights into CAR T-cell-mediated remodelling of the TNBC TME and inform the development of new CAR T-cell therapies for TNBC and other solid tumours.