Tumor characteristics of dissociated response to immune checkpoint inhibition in advanced melanoma.

Stage IV melanoma patients treated with ICI and dissociated response were retrospectively screened for available samples containing sufficient tumor at least at two time-points. Included were one patient with metachronous regressive and progressive lesions at the same site, two patients with regressive and novel lesion at different sites, and three patients with regressive and progressive lesions at different sites. In addition, four patients with acquired resistant tumor samples without a matched second sample were included.

Intrapatient comparison of progressive versus regressive lesions indicates no defect in tumor T cell infiltration, and in general no tumor immune exclusion were observed.

In the majority of patients, the progressive tumor lesion contained higher CD8⁺ T cell counts/mm² and interferon-gamma (IFNγ) signature level, but similar tumor PD-L1 expression. The tumor mutational burden levels were in 2 out 3 lesions higher compared to the corresponding regressive tumors lesion. In the acquired tumor lesions, high CD8⁺/mm² and relatively high IFNγ signature levels were observed. In one patient in both the B2M and PTEN gene a stop gaining mutation and in another patient a pathogenic POLE mutation were found.

Immune checkpoint inhibition (ICI) has improved patients' outcomes in advanced melanoma, often resulting in durable response. However, not all patients have durable responses and the patients with dissociated response are a valuable subgroup to identify mechanisms of ICI resistance.