Cole, Megan; (2025) Investigating immune evasion in KRAS mutant lung cancer through spatial proteomic analysis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Although the survival rate of lung cancer patients has improved in recent years due to the approval of immune checkpoint blockade and KRAS-G12C inhibitors, only a subset of patients responds. Unfortunately, for those that do, durable response is rare due to resistance onset. In this study, we aimed to provide rationale for new therapeutic combinations with KRAS-G12C inhibitors that are desperately needed to tackle the issue of resistance and improve patient survival. We studied the immune refractory Lewis Lung carcinoma (3LL) tumour microenvironment using imaging mass cytometry where we observed remodelling to favour anti-tumoural immune response following KRAS-G12C inhibition, despite lack of tumour regression. By clustering based on neighbour information to generate spatial communities, we were able to pinpoint recurring spatial patterns that were rich for CD8+ T cells, known to be essential components of anti-tumoural immune response. We then focused on the T cell and dendritic cell rich (T/DC) community, which resembled an immune activation hub. However, further analysis revealed enrichment of Tregs within this community, specifically in the CD8+ T cell neighbourhood. Separating the T/DC community based on Treg presence revealed that Treg cells may be acting to dampen CD8+ T cell-mediated anti-tumoural immune responses, providing rationale to combine KRAS-G12C inhibition with Treg depletion. This rationale was validated through analysis of treatment naïve NSCLC patient samples and follow-up in vivo experiments where Treg depletion was combined with KRAS-G12C inhibition and anti-PD-1 therapy. Subsequent spatial analysis of the immunogenic KPAR model revealed multiple communities similar to the 3LL T/DC group, with one community in particular sharing resemblance across CD8+ T cell neighbourhood enrichment patterns. The unique component of this community involved the spatial enrichment of B cells and tertiary lymphoid structure presence, which may be driving increased responses in the KPAR model that is lacking in the 3LL tumours.

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