ImmuneMetTx

Immune checkpoint inhibitors (CPIs), which have revolutionised the treatment of metastatic NSCLC and other tumour types, increase the anti- tumour immune response through T-cell activation. However, clinical experience has revealed that more than 50% of patients present with intrinsic or develop acquired treatment resistance to immune therapies. It is unclear whether immunoediting, a set of processes that cause selection for cancer cells resilient to immune attacks, play an essential role in CPI resistance. To properly study immunoediting through cancer progression, it is essential to reconstruct the evolutionary history of cancer cell-intrinsic immunoediting processes - for example through loss of HLA alleles-, and the roles played by the tumour microenvironment in mediating immune selection pressures. To do that, comprehensive sampling and characterisation of a clinical cohort of primary tumours and the corresponding metastases are needed. Such datasets are scarce and where available, include data from only a few individuals
In this project, I aim to quantify mechanisms of immunoediting in longitudinal multi-region samples collected at the time of surgery, relapse, and autopsy to answer fundamental questions about how the immune system shapes cancer evolution and the role of immunoediting in CPI failure. This analysis will be made possible by the TRACERx, PEACE studies and the DARWIN II clinical trial, managed by the host lab. I will integrate different data, including 500X whole-exome sequencing, Imaging Mass Cytometry, evolutionary reconstruction and detailed clinical annotation, to do an unprecedented analysis of the spatial and temporal heterogeneity of immunoediting mechanisms, and how they relate to features of the cancer genome, transcriptome, tumour microenvironment and CPI responses.