Peripheral Blood Mononuclear Cells Profiling Revealed Biomarkers That Predict PD‐1 Inhibitor‐Induced Immune‐Related Adverse Events

ABSTRACT Immune checkpoint inhibitors (ICIs) universally enhance antitumor immunity but endanger a subgroup of patients by triggering immune‐related adverse events (irAEs). We profiled the expressions of 41 proteins on peripheral blood mononuclear cells (PBMCs) prior the initiation of immunotherapy. CXCR3 and CCR6 expressions were significantly decreased in PBMC subpopulations from patient with irAEs but not from those who responded to PD‐1 inhibitors. The expression of CCR6 in a NK cell subpopulation serves exclusively as a biomarker to differentiate patients who developed irAEs. Interestingly, circulating ligands of CXCR3, including CXCL9, CXCL10, and CXCL11, were significantly increased in patients who later developed irAEs after PD‐1 inhibitor treatment. The decreases of CXCR3 in three T cell subpopulations and decreases of CCR6 in a NK cell subpopulation were further validated in two independent external cohorts. Moreover, multiple proteins in PBMCs, distinct from the irAE‐predicting biomarkers, exhibited differential expression levels corresponding to the differential responses to the PD‐1 inhibitors. Via multiple independent cohorts, our study revealed crucial roles of CXCR3 and CCR6 in PD‐1‐induced irAEs, provided potential circulating biomarkers associated with toxicity and responses of PD‐1 inhibitors and further sculptured the landscape of immune cell heterogeneity via focusing on PBMC subpopulations.