What We propose to use pre-invasive pulmonary neoplasia (PID) as a model to examine dysfunctional neoepitope-specific T cell responses (Tneo) during tumour formation, to define actionable, rational targets for early or prophylactic T cell reprogramming. This will inform how to tune early immune responses to prevent or halt cancer formation, and ultimately guide future clinical strategies in early intervention immunotherapy or cancer immuno-prevention. Why Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide, with only 1 in 10 patients surviving the decade post diagnosis. Targeting dysfunctional responses to mutation derived neoantigens via checkpoint inhibition (CPI) improves clinical outcomes, yet these agents remain ineffective in the majority of patients (60-80%), highlighting the need to advance immunotherapy protocols. The pre-invasive setting offers the potential to prevent lung cancer, but early detection and treatment regimens are yet to be optimised. How We will test whether systemic or lesion-infiltrating T cells recognize neoantigens or mutant airway clones and define, for the first time, the key inhibitory or stimulatory molecules to target on neoepitope specific CD4 and CD8 T cells (Tneo). We will examine the T cell reactivity in PID, to determine which tumour antigens are detected in the early immune response. Based on this we will identify intra-lesional tumour reactive T cell populations in patients with high-grade lesions of the airways and define their molecular characteristics to identify novel targets. Finally we will examine T cell reactivity in pre- and post treatment blood samples of PID patients treated with checkpoint inhibition with PID assess how T cell responses are linked to selective progression and regression of lesions.