PD‐L1 on large extracellular vesicles is a predictive biomarker for therapy response in tissue PD‐L1‐low and ‐negative patients with non‐small cell lung cancer

Abstract

AbstractImmunotherapy has revolutionized the treatment of patients with non‐small cell lung cancer (NSCLC). High expression of tissue PD‐L1 (tPD‐L1) is currently the only approved biomarker for predicting treatment response. However, even tPD‐L1 low (1‐49%) and absent (<1%) patients might benefit from immunotherapy but, to date, there is no reliable biomarker, that can predict response in this particular patient subgroup. This study aimed to test whether tumour‐associated extracellular vesicles (EVs) could fill this gap. Using NSCLC cell lines, we identified a panel of tumour‐related antigens that were enriched on large EVs (lEVs) compared to smaller EVs. The levels of lEVs carrying these antigens were significantly elevated in plasma of NSCLC patients (n = 108) and discriminated them from controls (n = 77). Among the tested antigens, we focused on programmed cell death ligand 1 (PD‐L1), which is a well‐known direct target for immunotherapy. In plasma lEVs, PD‐L1 was mainly found on a population of CD45−/CD62P+ lEVs and thus seemed to be associated with platelet‐derived vesicles. Patients with high baseline levels of PD‐L1+ lEVs in blood showed a significantly better response to immunotherapy and prolonged survival. This was particularly true in the subgroup of NSCLC patients with low or absent tPD‐L1 expression, thus identifying PD‐L1‐positive lEVs in plasma as a novel predictive and prognostic marker for immunotherapy.