CD14+CD16−HLA-DRhi monocyte frequency was linked to response to anti–PD-1 in patients with melanoma.
Major finding: CD14+CD16−HLA-DRhi monocyte frequency was linked to response to anti–PD-1 in patients with melanoma.
Approach: High-dimensional single-cell mass cytometry characterizes PBMCs before and after anti–PD-1 treatment.
Impact: Monocyte frequency in PBMCs may identify patients with melanoma likely to benefit from anti–PD-1 therapy.
Immune checkpoint blockade targeting PD-1 achieves dramatic increases in progression-free survival in a subset of patients with metastatic melanoma and other tumor types. However, many patients do not achieve durable response, and biomarkers to predict clinical response are lacking. Krieg and colleagues used high-dimensional single-cell mass cytometry and a customized bioinformatics pipeline to discover biomarkers in peripheral blood mononuclear cells (PBMC) from 20 patients with stage IV melanoma before and after 12 weeks of anti–PD-1 therapy compared with 10 healthy donors. The frequency of myeloid cells predicted responses to anti–PD-1 treatment, with responders having higher frequencies of CD14+CD16−HLA-DRhi monocytes before therapy and a lower frequency of circulating T cells. Further, anti–PD-1 therapy induced a response signature in the T-cell compartment. Responders had higher numbers of CD4+ T cells expressing PD-1, IL4, IFNγ, IL10, IL17A, and Grz-B than nonresponders after one cycle of anti–PD-1 treatment. Similarly, CD8+ T cells upregulated CTLA4, granzyme B, CD11a, and CCR4 in responders as compared to nonresponders, which also showed higher migratory capacities. Subsequent CD4 or CD8 T-cell phenotypes were of central or effector memory cells. Results were validated by using conventional flow cytometry in an independent cohort of 31 patients. Finally, a hazard model revealed that a monocyte frequency of greater than 19.38% before therapy initiation was associated with a better response, extended progression-free and overall survival. Taken together, these findings reveal that elevated monocyte frequencies may be a potential biomarker for response to anti–PD-1 treatment.
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