Neoadjuvant immune checkpoint inhibitor (NeoICI) therapy improves clinical outcomes for people with early-stage, resectable non-small cell lung cancer (NSCLC) and has now been incorporated into standard-of-care. Patients receiving NeoICI will exhibit a range of tumour regression, up to a complete pathologic response (pCR), which correlates with increased survival. Even for patients without a pCR, there is emerging evidence that the magnitude of pathologic response is a surrogate for long-term benefit, including survival. However, the precise predictive factors and molecular pathways correlated with these incremental pathologic responses (PR) are not known.
The objective of this study was to examine the relationship between bulk or spatially-defined immune compartments and NeoICI response in resectable NSCLC.
POPCORN is a phase 1B/2 trial in people with stage IB-IIIA NSCLC receiving NeoICI prior to surgical resection. To address molecular mechanisms of response, an integrated multi-modal translational study assessed infiltrating immune cells from freshly-isolated, disaggregated tumour using high-content spectral flow cytometry panels (Aurora Cytec) while spatial transcriptomic and proteomic profiles were assessed on surgical samples using the Nanostring CosMx 6k SMI platform and the Akoya/CODEX high-plex protein platform.
We observed that the frequency and activation phenotype of immune cells from patients achieving a pronounced (>50%) PR was elevated relative to those patients with a pCR or <50% PR, reflecting the on-going and active immune response. Using cell neighbourhood (CN) analysis (Scdney R LisaClust function), we identified three spatially-organized immune/tumour CNs which correlated with degree of PR.
Altogether, this study shows the integration of multi-modal spatial and bulk analysis can inform mechanisms related to degree of response to NeoICI therapy and may help tailor long-term patient follow-up and adjuvant treatment strategies.