Editors' Picks

        Pathogen alert

        Memory T cells, which are generated during an infection, migrate through extralymphoid regions and lie in wait to mount a swift and strong response after another encounter with the pathogen. Recent studies have focused on memory T cells that permanently reside in the periphery and are termed tissue-resident memory cells (TRM cells). They offer an attractive target for the development of vaccines, despite our general lack of understanding of the mechanisms by which small numbers of these cells can protect expansive peripheral tissues. In a recent issue of Science, three groups reported findings related to the mechanisms governing the persistence and protective function of TRM cells. Iijima and Iwasaki demonstrated that preexisting CD4 TRM cells in the genital mucosa were necessary for full protection from a lethal herpes simplex virus 2 infection, and that macrophage-derived chemokines maintained this cell population in memory lymphocyte clusters distinct from the circulating cells. Schenkel and colleagues demonstrated that CD8 TRM cells act as early sensors of infection and generate broad alarming functions. Furthermore, Ariotti and colleagues found that triggering of TRM cells—previously created in mice via intraepidermal DNA vaccination—with peptide antigen led to a rapid alteration in the transcriptome even before the subsequent influx of immune cells. Activation of these cells induced numerous factors with broad antiviral and antibacterial activities. The tissue conditioning that results from activation of TRM cells led to enhanced pathogen control from other antigenically unrelated pathogens. These data demonstrate that this tissue conditioning is almost immediate, forms an effective amplification system to induce a tissue-wide response, and results in antigen-independent protection, which effectively minimizes viral escape. Together, these reports demonstrate that TRM cells act to bridge the adaptive and innate immune systems by triggering a state of tissue-wide pathogen alert and, as such, provide an attractive target for the design of strategies to halt pathogens before infection establishment. (Science 346:40–1, 2014; Science 346:93–8, 2014; Science 346:98–101, 2014; Science 346:101–5, 2014) Selected by L. Beck

        Targeting the linchpin

        The proinflammatory IL-17A has been suggested to be the master cytokine that functions in the pathogenesis of psoriasis to stimulate keratinocytes to secrete chemokines and inflammatory molecules, which recruit additional inflammatory cells. Results of previous clinical trials of IL-17A inhibitors support the notion that this cytokine is crucial in other immune-mediated disorders as well. On the tail of basic research and early clinical studies, Langley and colleagues conducted two randomized phase III trials (a two-dose comparison in ERASURE and a full-year investigative comparison in FIXTURE) to assess the efficacy and safety of secukinumab, a recombinant fully humanized immunoglobulin G1κ monoclonal antibody that neutralizes IL-17A. Secukinumab was associated with a rapid reduction in disease symptoms, higher PASI 75 rates, and high response rates in a majority of patients through week 52. In addition, secukinumab was superior to the tumor necrosis factor etanercept. Thus, secukinumab proved to be effective for treating psoriasis in both studies, supporting the importance of IL-17A in psoriasis pathogenesis and as a treatment target. (N Engl J Med 371:326–38, 2014) Selected by T. Schwarz

        Two is better than one

        Inhibition of the MAPK pathway with BRAF inhibitors (dabrafenib) improves the survival of metastatic melanoma patients who harbor the BRAF V600 mutation; however, the majority of these patients develop resistance to treatment via reactivation of the MAPK pathway. Previous preclinical and phase II studies indicated that inhibition of this signaling pathway using both BRAF and MEK inhibitors (trametinib) delayed the emergence of resistance and decreased the development of cutaneous hyperproliferative lesions, which often occur with MAPK signaling reactivation. Long and colleagues conducted a double-blind, randomized phase III study to determine the efficacy of a combination of dabrafeib and trametinib as a first-line therapy of 423 metastatic melanoma patients with a BRAF V600E or V600K mutation. This combination treatment induced a 25% relative reduction in the risk of disease progression and resulted in a significantly higher overall response rate in these patients than in patients treated with dabrafenib alone. These findings demonstrate that inhibition of the MAPK pathway at two distinct points decreases the risk of progression and thereby delays resistance in metastatic melanoma patients. (N Engl J Med 371:1877–88, 2014) Selected by B.A. Gilchrest

        Risky business

        Telomere length, which decreases with age as well as after exposure to UV radiation and smoking, has been associated with risk of age-associated diseases, including cancers. For melanoma, longer telomeres have been associated with increased risk and increased number of nevi, which is a significant risk factor for melanoma development. Although genetic variants—single-nucleotide polymorphisms (SNPs)—have been identified in association with telomere length in a meta-analysis, Iles and colleagues recently investigated these variants in 11,108 cases and 13,933 controls in a genome-wide association study of melanoma. Four of the seven SNPs were significantly associated with melanoma risk based on a calculated genetic score that predicts telomere length. These results support the hypothesis that genetic factors that influence telomere length have a strong effect on melanoma risk, with a longer telomere length predisposing melanoma. (J Natl Cancer Inst 106:dju267, 2014) Selected by B.A. Gilchrest