Abstract 1302P
Background
Lung cancer is the leading cause of cancer related mortality in men and second cause of cancer mortality in women, with 5-year survival rates of 15%. Of these cases, durable responses to PD-1/PD-L1 directed immune checkpoint therapies are observed in only 20-30%. Both PD-L1 expression and tumour mutation burden are FDA approved diagnostic biomarker tests used to stratify patients for immunotherapy, however they perform poorly, indicating that much remains to be discovered regarding mechanisms that dictate therapy response. There remains a rneed for informative methods to analyse both cellular composition and spatial organisation in tissue beyond standard immunohistochemistry.
Methods
Here we examined the composition of patient tumours (n=41) from a second-line immunotherapy (IO) cohort using Nanostring spatial profiling (DSP). Over 1800 mRNAs and 70 proteins were analysed within separate tumour or stroma compartments of each TMA core, and our analysis utilised unbiases approaches to identify factors that may influence patient response.
Results
Differential analysis between responders and non-responders indicated several novel features. IL2 mRNA in stroma aswell as IL2 receptor (CD25) in both tumour and stroma were significantly upregulated in patients who responded (stroma IL-2, p=0.0004, tumour CD25, p=0.0095; stroma CD25, p=0.022). CD24 and JUP mRNA were significantly decreased in tumours of responding patients, while SHC3, SPP1, and MAGEA4 were significantly higher in stroma of these patients. In addition, IDO1 protein was significantly increased in stroma of non-responding patients, consistent with the role that the suppression of T-cell activation may have in dictating therapy response. CD44 protein was reduced in tumours of responding patients, which coincided with the significant increase of its extracellular matrix (ECM) ligand, SPP1 (osteopontin) in the stroma.
Conclusions
Overall, these data indicate the potential activation of stroma in responding patients, and is characterised by the enhanced interleukin (IL2, IL33) signalling activity which may act downstream of the changes in T-cell responses in the subset of patients who respond to PD-1/PD-L1 immune checkpoint blockade.
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.