SPACETIME · SPatial Analysis of Cancer Evolution in the Tumour Immune MicroEnvironment

The introduction of immune checkpoint therapy for Non-Small Cell Lung Cancer (NSCLC) has improved clinical outcomes. However, due to primary or secondary resistance, only a minority of patients show long term responses, leading to exploration of a multiplicity of new agents and combinatorial strategies. Due to lack of biomarkers that can predict response, many patients are submitted to treatments that will not have clinical benefit. A thorough understanding of the biological processes causing resistance to immunotherapy in NSCLC could facilitate informed personalised therapy choices. This requires a multifactorial assessment of the tumour microenvironment, a complex and dynamic milieu, encompassing the majority of tumour-host interactions. SPACETIME brings together interdisciplinary expertise to achieve a superior understanding of the spatial and temporal tumour-host co-evolution, and drive translation into predictive biomarkers for precision immunotherapy. We will integrate spatial proteomics, transcriptomics, metabolomics and glycomics to analyse patient biopsies from early stage to metastatic disease, complemented with tissues from representative mouse models to cover the developments early after tumour initiation. Environmental and systemic factors that may influence this co-evolutionary process will be included to identify potential risk factors for therapy resistance. Ex-vivo, in vitro and in vivo assays will bring functional understanding of immune resistance mechanisms and identify key cellular interactions and therapeutic targets. This will be brought together by advanced computational approaches, to define spatial signatures, that will lead to a limited panel of potential prognostic and/or predictive markers for immunotherapy. Supported by engagement of key stakeholders, SPACETIME will pave the way towards development of a spatial signature test for patient stratification, to sidestep immunotherapy resistance and improve survival for NSCLC patients.This action is part of the Cancer Mission cluster of projects on “Understanding (tumour-host interactions)”.