Abstract
BackgroundThe immunotherapy with immune checkpoints inhibitors (ICI) has changed the life expectancy in metastatic melanoma (MM) patients. Nevertheless, several patients do not respond hence, the identification and validation of novel biomarkers of response to ICI is of crucial importance. Circulating extracellular vesicles (EVs) such as PD-L1+ EV mediate resistance to anti-PD1, instead the role of PD1+ EV is not fully understood.MethodsWe isolated the circulating EVs from the plasma of an observational cohort study of 71 metastatic melanoma patients and correlated the amount of PD-L1+ EVs and PD1+ EVs with the response to ICI. The analysis was performed according to the origin of EVs from the tumor and the immune cells. Subsequently, we analysed the data in a validation cohort of 22 MM patients to assess the reliability of identified EV-based biomarkers. Additionally we assessed the involvement of PD1+ EVs in the seizure of nivolumab and in the perturbation of immune cells-mediated killing of melanoma spheroids.ResultsThe level of PD-L1+ EVs released from melanoma and CD8+ T cells and that of PD1+ EVs irrespective of the cellular origin were higher in non-responders. The Kaplan-Meier curves indicated that higher levels of PD1+ EVs were significantly correlated with poorer progression-free survival (PFS) and overall survival (OS). Significant correlations were found for PD-L1+ EVs only when released from melanoma and T cells. The multivariate analysis showed that high level of PD1+ EVs, from T cells and B cells, and high level of PD-L1+ EVs from melanoma cells, are independent biomarkers of response. The reliability of PD-L1+ EVs from melanoma and PD1+ EVs from T cells in predicting PFS was confirmed in the validation cohort through the univariate Cox-hazard regression analysis. Moreover we discovered that the circulating EVs captured nivolumab and reduced the T cells trafficking and tumor spheroids killing.ConclusionOur study identified circulating PD1+ EVs as driver of resistance to anti-PD1, and highlighted that the analysis of single EV population by liquid biopsy is a promising tool to stratify MM patients for immunotherapy.
Highlights
The immunotherapy with immune checkpoints inhibitors (ICI) has changed the life expectancy in metastatic melanoma (MM) patients
We discovered that a significant increase of circulating uPAR+ extracellular vesicles (EVs) released from melanoma, C D8+ T-cells and dendritic cells correlated with unresponsiveness in a cohort of MM patients subsequently treated with nivolumab or pembrolizumab, further supporting the notion that EV-based biomarkers are powerful tool to predict innate resistance to ICI [25]
Observational cohort: patient characteristics and outcomes to ICI therapy are summarised in Table 1, whose data are already reported in [25] in which the same series of patients were screened to profile the circulating u PAR+ EVs
Summary
The immunotherapy with immune checkpoints inhibitors (ICI) has changed the life expectancy in metastatic melanoma (MM) patients. Patient’s selection for immunotherapy is based on the PD-L1 expression [3] and on the genomic assessment of tumor mutational burden [4] Despite both are predictors of a better response to ICI, they are not fully satisfactory because such evaluations are not effective in capturing the dynamic spatial and temporal heterogeneity of the tumor [5] and they return indistinct antigenic value of individual mutations [6]. In terms of candidate predictors, growing interest has been focusing on the exploitation of circulating extracellular vesicles (EVs), released by both normal and cancer cells for the clinical assessment of patients [7, 8]
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