Editors' Picks

        Double whammy

        Recent developments in the treatment of metastatic melanoma have included immune checkpoint–blocking antibodies, such as the anticytotoxic T-lymphocyte-associated antigen 4 antibody ipilimumab, as well as antiprogrammed death 1 antibodies, such as nivolumab. Because these agents have exhibited complementary activity in previous phase II studies, Larkin and colleagues conducted a randomized, double-blind, multicenter, phase III trial to evaluate the safety and efficacy of nivolumab alone or nivolumab combined with ipilimumab in patients with previously untreated metastatic melanoma. Treatment with nivolumab alone or in combination with ipilimumab induced longer progression-free survival and higher objective response rates than treatment with ipilimumab alone. The progression-free survival observed for the combination therapy was in line with that reported following combined BRAF and MEK inhibition. Moreover, although a high percentage of patients experienced adverse events, management of these events was mostly successful, highlighting the potential for safe use of this combination therapy in a broad range of clinical settings. (N Engl J Med 373:23–34, 2015) Selected by P. Nghiem

        Antigen-specific twins

        Both resident memory T (Trm) cells, which reside in peripheral tissues, and central memory T (Tcm) cells, which reside in lymph nodes, play a role in protective immunity; however, the origins of these distinct cell types remain unclear. Gaide and colleagues employed skin immunization with a contact sensitizer hapten, a protein, and a virus to probe the cell origins of Trm and Tcm cells in mice. The tissue Trm cell compartment responded rapidly in a tissue-specific response to antigen. The Tcm compartment gained effector function more slowly, although these cells were competent to supplement the Trm cells after antigen challenge. CDR3 sequence analysis supports the existence of a naive T-cell precursor common to Trm and Tcm cells. Together, these findings suggest that, after skin immunization, TCR-identical, antigen-reactive T cellsare distributed to both lymph nodes as Tcm and to peripheral tissues as Trm cells to yield two distinct memory T-cell compartments with identical antigen specificity but unique effector characteristics. (Nat Med 21:647–53, 2015) Selected by T. Schwarz

        Skin-resident bacteria calibrate immunity

        An immune presence in the skin is essential for maintaining an effective barrier to pathogens, but this homeostasisoccurs with continuous contact with a diverse commensal microbiota. Naik and colleagues recently reported that the skin represents a highly dynamic immune environment that is actively and finely calibrated by defined commensal species. Tissue-resident dendritic cells were identified as the primary sensors of fluctuations in the commensal bacterial community and ultimately coordinate the generation of commensal-specific T-cell responses, providing a powerful protective mechanismfor host defense via establishment of heterologous immunity against potentially invasive microbes. These findingsare intriguing in the context of skin diseases because commensal-specific immune responses were found to rely on the production of IL-17A, which contributes to the etiology and pathology of various skin inflammatory disorders, such as psoriasis. (Nature 520:104–8, 2015) Selected by T. Schwarz

        After the sun goes down

        Although melanin offers protection from sunlight-induced DNA damage and skin cancer, this pigment is not necessarilybeneficial. Most mutations in human melanomas exhibit cyclobutane pyrimidine dimers (CPDs) that arisemainly from UVB exposure because UVA is less likely to generate these signature lesions. Premi and colleagues,however, recently found that exposure of melanin-containing cells to UVA radiation induces reactive oxygen andnitrogen species that degrade melanin, induce the appearance of melaninlike granules in the nucleus, and excitemelanin derivatives to a triplet state with the high energy of a UV photon. Furthermore, these effects occur for manyhours after the original UV exposure, allowing these excited products to essentially create CPDs in the dark. Thus,melanin may be carcinogenic as well as protective against melanoma. These mechanistic findings provide an avenue for exploration of novel triplet quenchers that may provide an ”evening after” sunscreen to halt the carcinogenicprocesses after UV exposure. (Science 347:842–7, 2015) Selected by T. Schwarz

        Genomic classification

        Prognosis is not favorable for patients with melanoma with regional metastases, despite the recent approval of inhibitors that target the frequently mutated MAPK pathway. To illuminate the biological heterogeneity of melanoma with hopes of improving prognosis and spurring development of novel therapeutic interventions, researchers from the Cancer Genome Atlas program performed a systematic, multiplatform characterization of 333 cutaneous melanomas from 331 patients at the DNA, RNA, and protein levels. The melanomas were classified based on identified significantly mutated genes into four main subtypes: BRAF, RAS, NF1, and Triple Wild-Type, which included tumors that lacked hot-spot mutations in BRAF, RAS, or NF1 but featured KIT mutations, local amplifications, and complex structural rearrangements. Consensus hierarchical clustering analysis revealed three additional subclasses. Interestingly, although no significant outcome correlation with genomic classification was found, postaccession survival of patients with regionally metastatic tumors was improved in the ”immune” transcriptomic subclass. (Cell 161:1681–96, 2015) Selected by M. Amagai