Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts.,By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease.,In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival.,Loss of both copies of B2M is found only in non-responders.,B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.,Resistance to immune-checkpoint blockade often occurs in treated patients.,Here, the authors demonstrate that B2M loss is a mechanism of primary and acquired resistance to therapies targeting CTLA4 or PD-1 in melanoma patients.
Acral melanoma (AM), as a peculiar subgroup of melanoma, is rare in Caucasians but has higher incidence in Asians.,Large series of study on AM with clinicopathological features and prognostic factors is still limited, especially in Asian population.,We retrospectively collected clinical, pathological and follow-up data of 142 AM cases.,All patients were Chinese, with the age ranging from 24 to 87 years (mean 62.0; median 62.0).,The Breslow thickness of primary lesions ranged from 0.6 to 16.3 mm (mean 4.9; median 3.7).,85.9% of the patients had acral lentiginous histologic subtype.,Plantar was the most frequently involved site, followed by heels.,Statistically, duration of the lesion before diagnosis (≤2.5 years), Breslow thickness >4.0 mm (T4), high mitotic index (>15 mm−2), presence of vascular invasion, regional lymph node metastasis at diagnosis and pathologic stage (II/III/IV) were found to be independent prognostic factors in both univariate and multivariate analyses.,The prognosis of AM in Chinese is extremely poor.,Our 5- and 10-year disease-specific survival (DSS) rates were 53.3% and 27.4%, respectively.,Therefore, AM in Asians represents a more biologically aggressive melanoma subtype and is thought to carry a worse prognosis when compared with other races or cutaneous melanomas in other anatomic sites.