IL-27 signaling activates skin cells to induce innate antiviral proteins and protects against Zika virus infection

In the skin, antiviral proteins and other immune molecules serve as the first line of innate antiviral defense. Here, we identify and characterize the induction of cutaneous innate antiviral proteins in response to IL-27 and its functional role during cutaneous defense against Zika virus infection. Transcriptional and phenotypic profiling of epidermal keratinocytes treated with IL-27 demonstrated activation of antiviral proteins OAS1, OAS2, OASL, and MX1 in the skin of both mice and humans. IL-27–mediated antiviral protein induction was found to occur in a STAT1- and IRF3-dependent but STAT2-independent manner. Moreover, using IL27ra mice, we demonstrate a significant role for IL-27 in inhibiting Zika virus morbidity and mortality following cutaneous, but not intravenous, inoculation. Together, our results demonstrate a critical and previously unrecognized role for IL-27 in cutaneous innate antiviral immunity against Zika virus

Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma

Background: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-Iymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS.Patients and methods: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry.Results: There was strong interobserver reproducibility in assessment of pathological response (kappa = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had >= 70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P = 70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.Analysis and support of clinical decision makin

The optimum excision margin and regional node management for primary cutaneous T3 melanomas (2-4 mm in Thickness): a retrospective study of 1587 patients treated at a single center.

Item does not contain fulltextOBJECTIVE: To determine the optimum excision margin and nodal management for patients with primary cutaneous melanomas 2.01- to 4.00-mm thick (T3 melanomas). BACKGROUND: Currently available evidence does not reliably define the minimum safe excision margin and best nodal management for patients with primary cutaneous T3 melanomas. METHODS: A retrospective study was conducted, analyzing data on 1587 patients with melanomas 2.01- to 4.00-mm thick treated at a single center. RESULTS: A histopathologic excision margin of 8 mm or more (equivalent to a >/=1 cm surgical margin) was associated with increased local and in-transit recurrence-free survival [hazard ratio (HR) = 0.54; P = 0.008] and disease-free survival (DFS) (HR = 0.59; P = 0.001) compared with a less than 8-mm margin. The /=1 cm surgical excision margin) combined with SLN biopsy (followed by an immediate completion lymph node dissection if positive) provided T3 melanoma patients with optimum local, regional, and distant disease control and resulted in enhanced melanoma-specific survival.1 december 201

Minimum Safe Pathologic Excision Margins for Primary Cutaneous Melanomas (1-2 mm in Thickness): Analysis of 2131 Patients Treated at a Single Center

Item does not contain fulltextOBJECTIVE: This study was designed to determine the minimum safe pathologic excision margin for primary cutaneous melanomas 1.01-2.00-mm thick (T2) and to identify prognostic factors that influence survival in these patients. BACKGROUND: Several studies have shown previously that "narrow" clinical excision margins (1-2 cm in vivo) are as safe as "wide" excision margins (4-5 cm) for management of primary T2 melanomas. However, pathologic margins are likely to be a better predictor of recurrence than clinical margins. METHODS: Clinicopathologic and follow-up data for 2131 T2 melanoma patients treated at Melanoma Institute Australia between January 1992 and May 2012 were analyzed. RESULTS: Of the 2131 patients, those who had a pathologic excision margin of /=8 mm (P = 0.049 and P = 0.045; respectively). However, these results failed to translate into a statistically significant difference in melanoma-specific survival. CONCLUSIONS: The results of this study suggest that if a peripheral/radial pathologic excision margin for a T2 primary cutaneous melanoma is <8 mm consideration should be given to performing a wider excision.11 p

Surgeons' opinions on lymphadenectomy in melanoma patients with positive sentinel nodes: a worldwide web-based survey

Item does not contain fulltextPURPOSE: A worldwide web-based survey was conducted among melanoma surgeons to investigate opinions about completion lymph node dissection (CLND) in patients with positive sentinel nodes (SN). METHODS: A questionnaire was designed following input from a group of melanoma surgeons. Cognitive interviews and pilot testing were performed. Surgeons identified through a systematic-review of the SN and CLND literature were invited by email. RESULTS: Of 337 surgeons, 193 (57.2 %) from 25 countries responded (January-July 2011). Most respondents work in melanoma (30.1 %) and surgical oncology (44.6 %) units. In patients with a positive SN, 169 (91.8 %) recommend CLND; the strength of the recommendation is mostly influenced by patient comorbidities (64.7 %) and SN tumor burden (59.2 %). Seventy-one responders enroll patients in the second Multicenter Selective-Lymphadenectomy Trial (MSLT-2), and 64 of them (76 %) suggest entering the trial to majority of patients. In cases requiring neck CLND, level 1-5 dissection is recommended by 35 % of responders, whereas 62 % base the extent of dissection on primary site and lymphatic mapping patterns. Only inguinal dissection or ilioinguinal dissection is performed by 36 and 30 % of surgeons, respectively. The remaining 34 % select either procedure according to number of positive SNs, node of Cloquet status, and lymphatic drainage patterns. Most surgeons (81 %) perform full axillary dissections in positive SN cases. CONCLUSIONS: The majority of melanoma surgeons recommend CLND in SN-positive patients. Surgeons participating in the MSLT-2 suggest entering the trial to the majority of patients. More evidence is needed to standardize the extent of neck and groin CLND surgeries

Representativeness of the Index Lymph Node for Total Nodal Basin in Pathologic Response Assessment After Neoadjuvant Checkpoint Inhibitor Therapy in Patients With Stage III Melanoma

IMPORTANCE Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a therapeutic lymph node dissection (TLND) can be safely omitted when a major pathologic response in the largest lymph node metastasis at baseline (index lymph node; ILN) is obtained is currently being investigated. A previous small pilot study (n = 12) showed that the response in the ILN may be representative of the pathologic response in the entire TLND specimen.OBJECTIVE To assess the concordance of response between the ILN and the total lymph node bed in a larger clinical trial population.DESIGN, SETTING, AND PARTICIPANTS Retrospective pathologic response analysis of a multicenter clinical trial population of patients from the randomized Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients (OpACIN) and Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) trials. Included patients were treated with 6 weeks neoadjuvant ipilimumab plus nivolumab. Patient inclusion into the trials was conducted from August 12, 2015, to October 24, 2016 (OpACIN), and November 24, 2016, and June 28, 2018 (OpACIN-neo). Data were analyzed from April 1, 2020, to August 31, 2021.MAIN OUTCOMES AND MEASURES Concordance of the pathologic response between the ILN and the TLND tumor bed. The pathologic response of the ILN was retrospectively assessed according to the International Neoadjuvant Melanoma Consortium criteria and compared with the pathologic response of the entire TLND specimen.RESULTS A total of 82 patients treated with neoadjuvant ipilimumab and nivolumab followed by TLND (48 [59%] were male; median age, 58.5 [range, 18-80] years) were included. The pathologic response in the ILN was concordant with the entire TLND specimen response in 81 of 82 patients (99%) and in 79 of 82 patients (96%) concordant when comparing the ILN response with the response in every individual lymph node. In the single patient with a discordant response, the ILN response (20% viable tumor, partial pathologic response) underestimated the entire TLND specimen response (5% viable, near-complete pathologic response). Two other patients each had 1 small nonindex node that contained 80% viable tumor (pathologic nonresponse) whereas all other lymph nodes (including the ILN) showed a partial pathologic response. In these 2 patients, the risk of regional relapse might potentially have been increased if TLND had been omitted.CONCLUSIONS AND RELEVANCE The results of this study suggest that the pathologic response of the ILN may be considered a reliable indicator of the entire TLND specimen response and may support the ILN response-directed omission of TLND in a prospective trial.Analysis and support of clinical decision makin

gamma delta T cells in merkel cell carcinomas have a proinflammatory profile prognostic of patient survival

Merkel cell carcinomas (MCC) are immunogenic skin cancers associated with viral infection or UV mutagenesis. To study T-cell infiltrates in MCC, we analyzed 58 MCC lesions from 39 patients using multiplex-IHC/immunofluorescence (m-IHC/IF). CD4⁺or CD8⁺ T cells comprised the majority of infiltrating T lymphocytes in most tumors. However, almost half of the tumors harbored prominent CD4/CD8 double-negative (DN) T-cell infiltrates (>20% DN T cells), and in 12% of cases, DN T cells represented the majority of T cells. Flow cytometric analysis of single-cell suspensions from fresh tumors identified DN T cells as predominantly Vδ2⁻ γδ T cells. In the context of γδ T-cell inflammation, these cells expressed PD-1 and LAG3, which is consistent with a suppressed or exhausted phenotype, and CD103, which indicates tissue residency. Furthermore, single-cell RNA sequencing (scRNA-seq) identified a transcriptional profile of γδ T cells suggestive of proinflammatory potential. T-cell receptor (TCR) analysis confirmed clonal expansion of Vδ1 and Vδ3 clonotypes, and functional studies using cloned γδ TCRs demonstrated restriction of these for CD1c and MR1 antigen-presenting molecules. On the basis of a 13-gene γδ T-cell signature derived from scRNA-seq analysis, gene-set enrichment on bulk RNA-seq data showed a positive correlation between enrichment scores and DN T-cell infiltrates. An improved disease-specific survival was evident for patients with high enrichment scores, and complete responses to anti-PD-1/PD-L1 treatment were observed in three of four cases with high enrichment scores. Thus, γδ T-cell infiltration may serve as a prognostic biomarker and should be explored for therapeutic interventions.See related Spotlight on p. 600Nicholas A. Gherardin, Kelly Waldeck, Alex Caneborg, Luciano G. Martelotto, Shiva Balachander, Magnus Zethoven ... et al