1952P - Multiomic spatial profiling of whole-slide NSCLC tissues from patients receiving anti PD-1 therapy identifies metabolic phenotypes associated with therapy resistance

Background

Non-small cell lung cancer (NSCLC) has a poor overall survival despite increases in targeted and systemic therapies. A subset of NSCLC patients treated with immune checkpoint inhibitor (ICI) therapy have shown benefit. However, most patients develop resistance. In order to better define both response and resistance profiles, deeper insights from the microenvironment are needed.

Methods

Here, we profiled spatially resolved, whole transcriptome and high-plex spatial proteomic profiling of whole-slide format NSCLC tissues (n=20) prior to single agent anti PD-1 therapy. The targeted protein panels covered tumour and immune cell typing, activation status, functional and metabolic profiles, in addition to cell signalling and apoptosis. Spatial compartments were contrasted to progression free survival (PFS) and overall survival (OS) according to RECIST criteria.

Results

The spatially resolved tumour compartments of poor responders (progressive disease - PD) to ICI showed increased expression of markers involved in ferroptosis (GPX-1, GPX-4) with dynamic levels of glucose uptake throughout the tumour (GLUT-1, G6PD) when contrasted to pathological complete responders (CR). Immune cell types including macrophages and CD8 T-cells were found on the periphery of these tumours, unable to infiltrate. Moreover, tumours from PD patients lacked lymphoid/tertiary lymphoid aggregates within or near the tumour area.

Conclusions

Taken together, this study shows the utility of spatial transcriptomic and proteomic profiling to glean insights into mechanisms driving tumour resistance in NSCLC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.