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Abstract
Background Immunotherapies, in particular, Immune checkpoint inhibitors (ICIs) have seen increasing adoption in non-small cell lung cancer (NSCLC), however their clinical benefit appears limited to a subset of patients that recieve benefit. Insights into the spatial localisation of immune cells and metabolic activation within tumours are key to understand the intercellular communications and the immune phenotypes that dictate the clinical outcome of these patients.
Methods We applied a tiered ultra-high plex spatial transcriptomics and proteomics approach to characterise the organization and interactions in NSCLC tissues from multiple retrospectively collected NSCLC patient cohorts that subsequently received PD-1 axis immunotherapy (figure 1).
Results Our RNA analysis revealed metabolic signatures associated with both response and resistance to therapy, highlighting an underlying mechanism underpinning resistance and sensitivity to therapy. Spatial proteomic profiling indicated that regulatory Tregs are enriched in non-responsive patients, and that this association is consistent with their localization within stromal and tumour-margin regions. Furthermore, close proximity interactions between Tregs and both monocytes (p=0.009) and CD8+ T cells (p=0.009) were more frequently found in non-responders, while macrophages were more frequently located in proximity HLADR+ tumour cells (p=0.01) within responder patients. Spatial compartmentalization of tissues into cellular neighbourhoods indicated specifically that both macrophages (p=0.003) and effector CD4+ T cells (p=0.01) in mixed tumour neighbourhoods, as well as CD8+ T cells (p=0.03) in HLADR+ tumour neighbourhoods are positively associated with response to ICI therapy. Evaluation of the inferred regulatory functions between immune cells relative to their tumour proximity by the SpatialScore metric suggests that macrophages may exhibit an immunosuppressive phenotype against both CD4+ and CD8+ T cells, and that this association is higher in non-responders, supporting dichotomous roles for macrophage polarisation in tumour progression.
Conclusions These spatial patterns are associated with overall survival in addition to ICI response and may thus indicate features relevant for the functional understanding of the tumour microenvironment that additionally inform upon patient stratification.
Ethics Approval This study has Queensland University of Technology (QUT) Human Research Ethics Committee approval (UHREC #2000000494) and University of Queensland ratification.
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