Eligibility for aPD1 therapy is based on PD-L1 expression, but few patients experience durable responses. Tumours cultured in microfluidic devices (tumour-on-chip) recapitulate the in vivo microenvironment and are being developed as drug screening platforms. Their application to advanced NSCLC is hampered by the unavailability of surgical tumour resection specimens in these patients. To overcome this, we aimed to develop a methodological approach that will allow culture of bronchoscopic tumour biopsies on chips to model drug responses.
Bronchoscopic biopsies from 25 NSCLC patients were dissected and filtered to obtain tumour spheroids of 40–100 μm in size (3 × 105 spheroids/biopsy). AIM biotech chips consisting of a central channel and 2 lateral channels were used. Tumour spheroids were dispersed in matrigel and split in the central channels of 2 chips. Endothelial cells were cultured at the lateral channels to mimic vasculature. Pembrolizumab (aPD1) vs isotype control was administered in the lateral channels (10 μg/mL). After 48 h effluents were analysed by cytometric bead array (CBA) for cytokines and cytotoxic molecules. Spheroids, along with effluents, were analysed by mass spectrometry (LC MS/MS).
CBA analysis showed a robust increase in the release of granzyme B and granulysin, used by T cytotoxic cells to kill cancer cells, in pembrolizumab-exposed effluents. LC MS/MS identified 122 differentially abundant proteins in pembrolizumab-treated vs control spheroids and 71 differentially abundant proteins in effluents. Pathway enrichment analysis suggested that pembrolizumab activated innate and adaptive immune responses and signal transduction pathways in bronchoBOCs.
We developed the first bronchoBOCs that develop physiologically-relevant responses to aPD1. We envisage to use bronchoBOCs for biomarker identification, as drug screening platform and to increase our mechanistic understanding of human tumour immunity.
Legal entity responsible for the study
B.S.R.C. Alexander Fleming.
ERA Per Med.
All authors have declared no conflicts of interest.