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Immune checkpoint inhibitors (ICI) have significantly improved overall survival in melanoma patients. However, 60% experience severe adverse events and early response markers are lacking. Circulating tumour DNA (ctDNA) is a promising biomarker for treatment-response and recurrence detection. The prospective PET/LIT study included 104 patients with palliative combined or adjuvant ICI. Tumour-informed sequencing panels to monitor 30 patient-specific variants were designed and 321 liquid biopsies of 87 patients sequenced. Mean sequencing depth after deduplication using UMIs was 6000x and the error rate of UMI-corrected reads was 2.47×10 -4 . Variant allele fractions correlated with PET/CT MTV (rho=0.69), S100 (rho=0.72), and LDH (rho=0.54). A decrease of allele fractions between T1 and T2 was associated with improved PFS and OS in the palliative cohort (p = 0.008 and p < 0.001). ctDNA was detected in 76.9% of adjuvant patients with relapse (n = 10/13), while all patients without progression (n = 9) remained ctDNA negative. Tumour-informed liquid biopsies are a reliable tool for monitoring treatment response and early relapse in melanoma patients with ICI., (© 2024. The Author(s).)

Rationale: Immune checkpoint inhibitor (ICI)-related pneumonitis is a serious autoimmune event affecting as many as 20% of patients with non-small-cell lung cancer (NSCLC), yet the factors underpinning its development in some patients and not others are poorly understood. Objectives: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. Methods: The study cohort consisted of patients with NSCLC who provided blood samples before and during ICI treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T-cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with NSCLC and patients with melanoma. Measurements and Main Results: Across both cohorts, patients in whom pneumonitis developed had higher pretreatment levels of immunoglobulin G autoantibodies targeting surfactant protein (SP)-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4 + IFN-γ-positive SP-B-specific T cells and expanding T-cell clonotypes recognizing this protein, accompanied by a proinflammatory serum proteomic profile. Conclusions: Our data suggest that the cooccurrence of SP-B-specific immunoglobulin G autoantibodies and CD4 + T cells is associated with the development of pneumonitis during ICI therapy. Pretreatment levels of these antibodies may represent a potential biomarker for an increased risk of developing pneumonitis, and on-treatment levels may provide a diagnostic aid.

Background & Aims: Despite the success of biological therapies in treating inflammatory bowel disease, managing patients remains challenging due to the absence of reliable predictors of therapy response., Methods: In this study, we prospectively sampled 2 cohorts of patients with inflammatory bowel disease receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry; single-cell RNA sequencing; single-cell variable, diversity, and joining sequencing; serum proteomics; and multidimensional flow cytometry to comprehensively assess vedolizumab-induced immunologic changes in the peripheral blood and their potential associations with treatment response., Results: Vedolizumab treatment led to substantial alterations in the abundance of circulating immune cell lineages and modified the T-cell receptor diversity of gut-homing CD4 + memory T cells. Through integration of multimodal parameters and machine learning, we identified a significant increase in proliferating CD4 + memory T cells among nonresponders before treatment compared with responders. This predictive T-cell signature demonstrated an activated T-helper 1/T-helper 17 cell phenotype and exhibited elevated levels of integrin α4β1, potentially making these cells less susceptible to direct targeting by vedolizumab., Conclusions: These findings provide a reliable predictive classifier with significant implications for personalized inflammatory bowel disease management., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In the phase 2 EMPOWER-CSCC-1 study (NCT02760498), cemiplimab demonstrated antitumor activity against metastatic cutaneous squamous cell carcinoma (mCSCC) and locally advanced cutaneous squamous cell carcinoma (laCSCC)., Objectives: To report final analysis of weight-based cemiplimab in mCSCC and laCSCC (groups 1 and 2), fixed-dose cemiplimab in mCSCC (group 3), and primary analysis of fixed-dose cemiplimab in mCSCC/laCSCC (group 6)., Methods: Patients received cemiplimab (3 mg/kg intravenously every 2 weeks [groups 1 and 2]) or cemiplimab (350 mg intravenously [groups 3 and 6]) every 3 weeks. The primary end point was objective response rate (ORR). Duration of response (DOR) and progression-free survival (PFS) are presented per protocol, according to post-hoc sensitivity analyses that only include the period of protocol-mandated imaging assessments., Results: At 42.5 months, ORR for groups 1-3 (n = 193) was 47.2%, estimated 12-month DOR was 88.3%, and median PFS was 26.0 months. At 8.7 months, ORR for group 6 (n = 165 patients) was 44.8%; median DOR and median PFS were not reached. Serious treatment-emergent adverse event rates (grade ≥3) were groups 1-3: 31.1% and group 6: 34.5%., Limitations: Nonrandomized study, nonsurvival primary end point., Conclusion: EMPOWER-CSCC-1 provides the largest prospective data on long-term efficacy and safety for anti-programmed cell death-1 therapy in advanced CSCC., Competing Interests: Conflicts of interest Dr Hughes reports consulting/advisory roles at AstraZeneca, Bristol-Myers Squibb, Eisai, Merck, Merck Sharp & Dohme, Pfizer, and Roche; and institutional research funding from Amgen. Dr Guminski reports personal fees and advisory board and travel support from Bristol-Myers Squibb and Sun Pharma; advisory board fees from Eisai, Merck KGaA, and Pfizer; travel support from Astellas; and clinical trial unit support from PPD Australia. Dr Bowyer reports advisory board roles for Eli Lilly Australia, Ipsen, Merck Sharp & Dohme, and Sanofi; virtual meeting sponsorship from Bristol-Myers Squibb and Merck Sharp & Dohme Australia; and travel support from Merck Sharp & Dohme and AstraZeneca. Michael Migden reports honoraria and travel expenses from Regeneron Pharmaceuticals, Inc., and Sanofi; consulting fees from Feldan Therapeutics, Replimune, Stamford Pharma, and Sun Pharma; and institutional research funding from Regeneron Pharmaceuticals, Inc., and Replimune. Dr Schmults reports steering committee membership for Castle Biosciences; steering committee membership and consultancy for Regeneron Pharmaceuticals, Inc.; consultancy for Sanofi; research funding from Castle Biosciences, Genentech, Merck, Novartis, and Regeneron Pharmaceuticals, Inc.; and serving as a chair for the National Comprehensive Cancer Network. Dr Khushalani reports grants and advisory board fees from Bristol-Myers Squibb, Merck, Novartis, and Regeneron Pharmaceuticals, Inc.; advisory board fees from AstraZeneca (data safety monitoring committee), Castle Biosciences, Incyte (data safety monitoring committee), Instil Bio, Iovance, Jounce Therapeutics, Nektar, and Replimune; grants from Celgene, GlaxoSmithKline, HUYA, Modulation Therapeutics, and Replimune; honoraria from Genzyme, National Comprehensive Cancer Network (grant funding from general research support through Pfizer), and Nektar (study steering committee); common stock ownership of Amarin, Bellicum Pharmaceuticals, and Transenetrix; study steering committee membership for Bristol-Myers Squibb, Regeneron Pharmaceuticals, Inc., and Replimune; and travel support from Regeneron Pharmaceuticals, Inc. Dr Chang reports consulting and advisory roles with Merck, and Regeneron Pharmaceuticals, Inc.; research funding from Galderma, Merck, Novartis, and Regeneron Pharmaceuticals, Inc., and consultancy for Castle Biosciences and Feldan. Dr Grob reports serving on an advisory board for Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Pfizer, Philogen, Roche, and Sanofi; and an advisory role for Bristol-Myers Squibb. Dr Lewis reports employment, stock, and other ownership interests at Regeneron Pharmaceuticals, Inc. At the time of this study, Dr Lewis was affiliated with the University of Colorado Denver Cancer Center and is now an employee of Regeneron Pharmaceuticals, Inc. Dr Day reports serving on an advisory board for Amgen, travel support from Merck; and clinical trial support (investigational medical product provision, no financial support) from AstraZeneca and Bristol-Myers Squibb. Dr Ladwa reports honoraria from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme; consulting or advisory roles for AstraZeneca, and Roche; and travel, accommodation, and expenses from Merck Sharp & Dohme. Dr Stein reports ownership of stocks/shares in Icon Group. Dr Muñoz Couselo reports serving on an advisory board for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; honoraria from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Roche; and clinical trial participation (principal investigator) for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi. Dr Meier reports travel support, speaker’s fees, or advisor’s honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; and research funding from Novartis and Roche. Dr Hauschild reports institutional grants, speaker’s honoraria, and consultancy fees from Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Pierre Fabre, Provectus, Roche, and Novartis; institutional grants and consultancy fees from Merck Serono, Philogen, and Regeneron Pharmaceuticals, Inc.; and consultancy fees from OncoSec. Dr Schadendorf reports honoraria from 4SC AG, Array BioPharma, Bristol-Myers Squibb, Immunocore, InflarxGmbH, Merck, Merck Sharp & Dohme, NeraCare GmbH, Novartis, Pierre Fabre, Pfizer, Philogen, Regeneron Pharmaceuticals, Inc., Sandoz, Sanofi, Serono, Sun Pharma, Roche/Genentech, and Ultimovacs; advisory board and consulting fees from 4SC AG, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., Roche/Genentech, Sanofi, and Nektar; speaker fees from Bristol-Myers Squibb, Merck KGaA, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., and Sanofi; institutional research funding from Array BioPharma/Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche; and travel/accommodation expenses from Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., Roche/Genentech, and Sanofi. Dr Basset-Seguin reports serving as an invited speaker, advisory board member, and consultant for Galderma, Regeneron Pharmaceuticals, Inc., Sanofi, and Sun Pharma. Dr Modi reports consulting/advisory board participation for Merck, Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme; and speaker bureau participation for Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme. Dr Dalac-Rat reports honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Sun Pharma. Dr Dunn reports advisory board participation for Merck and Regeneron Pharmaceuticals, Inc.; and research support from CUE-101, Regeneron Pharmaceuticals, Inc., Replimune Pharmaceuticals, and Seagen. Dr Flatz reports research funding from Hookipa Pharma; and advisory board fees from Bristol-Myers Squibb, Novartis, Philogen, and Sanofi. Dr Mortier reports personal fees and nonfinancial support from Bristol-Myers Squibb, and Merck Sharp & Dohme, Novartis, and Roche. Dr Guégan reports consulting fees from Bristol-Myers Squibb, Janssen, and Pierre Fabre; and technical support for congress attendance from Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, and Sanofi. Dr Heinzerling reports consulting fees from Bristol-Myers Squibb, Highlight Therapeutics, Novartis, Pierre Fabre, Roche, and Sanofi; lecture fees from Astellas, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche, and Sanofi; and travel grants from Bristol-Myers Squibb, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, and Roche. Dr Mehnert reports advisory board fees from Bristol-Myers Squibb, Eisai, Novartis, Pliant Therapeutics, Regeneron Pharmaceuticals, Inc., and Seagen; and consultancy fees from Merck. Dr Soria-Rivas reports speaker’s honoraria from Bristol-Myers Squibb, Immunocore, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche Pharma, and Sanofi Aventis; and advisory board fees from Bristol-Myers Squibb, Immunocore, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., and Sanofi Aventis. Dr Stratigos reports advisory board or steering committee roles for Janssen, Regeneron Pharmaceuticals, Inc., Roche, and Sanofi; and research support from AbbVie, Bristol-Myers Squibb, Genesis Pharma, LEO Pharma, Novartis, and Pfizer. Dr Ulrich reports advisory board and speaker roles for Regeneron Pharmaceuticals, Inc., Roche, Sanofi, and Sun Pharma. Dr Wong reports grant funding to institution from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, F-Star Therapeutics, Genentech, Gilead, Kura Oncology, Merck Sharp & Dohme, Pfizer, Regeneron Pharmaceuticals, Inc., and TopAlliance Biosciences, and consulting fees from Blueprint Medicines Corporation, Genzyme/Sanofi, and Regeneron Pharmaceuticals, Inc. Dr Beylot-Barry reports institutional research funding from Roche and speaker honoraria from Sun Pharma. Dr Bossi reports advisory board or conference honoraria for Merck, Merck Sharp & Dohme, Sanofi-Regeneron, and Sun Pharma. Dr Bugés Sánchez reports personal fees from Amgen, Merck, Novartis, and Sanofi. Dr Chandra reports honoraria from Array BioPharma, Bristol-Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi; consulting/advisory roles for Array BioPharma, Bristol-Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi; and institutional research funding from Bristol-Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi. Dr Robert reports grants, personal fees, and advisory board roles for Amgen, Biothera, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and Ultimovacs. Dr Silk reports institutional research grant and funding from Biohaven Pharmaceuticals, Merck, Morphogenesis, Regeneron Pharmaceuticals, Inc., Replimune, and Shattuck Laboratories; advisory board fees from Natera, Merck and Regeneron Pharmaceuticals, Inc.; consulting fees from Leerink, and royalties from UpToDate, Inc. Ms Booth and Drs, Yoo, Seebach, Lowy, and Fury report employment, stock, and other ownership interests at Regeneron Pharmaceuticals, Inc. Dr Rischin reports institutional research grant and funding from ALX Oncology, Bristol-Myers Squibb, GlaxoSmithKline, Kura Oncology, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Roche, and Sanofi; and uncompensated scientific committee and advisory board roles for Eisai, Bicara, GlaxoSmithKline, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., and Sanofi. Drs Ansstas, Trabelsi, and Russell have no conflicts of interest to declare., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

It is known, that different metastatic organ systems respond differently to immune checkpoint inhibitors (ICIs). In this study, we aimed to investigate the extent to which skin/subcutaneous metastases respond to ICI or targeted therapies (TTs) and whether the response rate differs from that of distant metastases in the same patient. Patients with melanoma diagnosed between January 2021 and September 2023 with at least one skin/subcutaneous metastasis who had received therapy with ICI or TT in an advanced setting were included in the analysis. Best overall response (BOR) was classified according to the revised response evaluation criteria in solid tumors (RECIST). The BOR of skin metastases and visceral metastases to ICI and TT was compared using the chi-square test. Skin metastases treated with ICI a first-line setting showed an overall response rate (ORR) of 44.1%. In contrast, visceral metastases had a higher ORR of 51.1%. However, the difference was not statistically significant (p = .77). Regarding TT, the ORR for skin metastases was 57.1%, compared to 38.5% for visceral metastases (p = .59). Interestingly, the ORR for skin/subcutaneous metastases was notably lower with ICI compared to visceral metastases, in contrast to patients who underwent TT. Skin metastases showed a poorer response to ICI than visceral metastases. Therefore, careful monitoring is recommended to detect non-response early in patients with skin metastases as skin metastases may have a worse response than TT. A larger cohort is needed for a comprehensive analysis and confirmation of our results., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Uveal melanoma is the most common malignant tumor of the eye in adults. About half of the patients develop distant metastases, most commonly liver metastases (>90%). These are associated with poorer overall survival compared to patients with extrahepatic metastases., Patients and Methods: In this retrospective study, patients diagnosed with metastatic uveal melanoma between January 2005 and December 2021 and treated at the Center for Dermato-oncology at the University of Tübingen, were included. The total cohort was divided into two groups. Group 1, in which the first diagnosis of metastasis was between 2005 and 2015 and group 2 with first metastasis between 2016 and 2021. Melanoma-specific survival (MSS) and progression-free survival (PFS) were calculated with the Kaplan-Meier method, test for differences was performed by the log-rank test., Results: A total of 167 patients were included in the study. Since more than 90% of patients had developed liver metastases as their first site of metastasis, we focused our analysis on patients with liver metastases. Median MSS was 28 months (95% confidence interval (CI) (22.8-33.2 months)) in patients receiving first-line liver-directed therapy ( n  = 89) compared to 10 months (95% CI (8.4-11.6 months)) for patients with first-line systemic therapy ( n  = 45). The best MSS was found in patients of group 2 and liver-directed therapy as first-line treatment. Since survival with first-line liver-directed therapy was significantly better in group 2, subsequent systemic therapies must also be considered, especially immune checkpoint inhibitors., Conclusion: This analysis revealed that MSS has improved significantly in recent years. In our analysis, first-line liver-directed therapy was associated with improved survival compared to first-line systemic therapy. Further studies are urgently needed, for example, to investigate the combination of immune checkpoint inhibition or tebentafusp with liver-specific procedures from the outset., Competing Interests: T.A. received institutional grants from SkylineDx, Neracare, Novartis, Sanofi, and consulting fees from Novartis, Neracare, BMS, CeCaVa, and Chemosat, outside the submitted work. U.L. received grants from MSD, honoraria as a speaker for MSD, Novartis, Sun Pharma, Sanofi, Roche, Almirall Hermal, and travel support from Sun Pharma, Pierre-Fabre, outside the submitted work. A.F. served as a consultant to Novartis, MSD, BMS, Pierre-Fabre and Immunocore; received travel support from Novartis, BMS, Pierre-Fabre, and received speaker fees from Novartis, Delcath, BMS and MSD and reports institutional research grants from BMS Stiftung Immunonkologie, outside the submitted work. L.F. reports grants or contracts from Hookipa Pharma, SAKK/Immunophotonics, DFG Grant (Deutsche Forschungsgemeinschaft), Philogen, and Mundipharma; consulting fees from Philogen, Sanofi, Novartis, BMS; participation on Data Safety Board University of Basel, all outside the submitted work. The other authors declare that they have no conflicts of interest., (© The Author(s), 2024.)

Tumor-associated antigens (TAAs) are potential targets for T cell-based immunotherapy approaches in cutaneous melanoma. BNT111, an investigational lipoplex-formulated mRNA-based therapeutic cancer vaccine encoding melanoma TAAs NY-ESO-1, tyrosinase, MAGE-A3, and TPTE, is undergoing clinical testing in adults. Expression of these TAAs in pediatric melanoma is unclear but is a prerequisite for feasibility of this treatment approach in children with melanoma. Our main objective was to characterize expression of those TAAs in pediatric melanomas compared to control cohorts. In this retrospective case control study, protein and transcript expression of NY-ESO-1, tyrosinase, MAGE-A3, and TPTE were analyzed in a cohort of 25 pediatric melanomas, 31 melanomas of young adults, 29 adult melanomas, and 30 benign melanocytic nevi in children using immunohistochemical staining and digital pathology (QuPath) and reverse transcription quantitative PCR. Based on IHC analysis, pediatric melanomas expressed tyrosinase (100.0%), TPTE (44.0%), MAGE-A3 (12.0%), and NY-ESO-1 (8.0%). Young adult melanomas expressed tyrosinase (96.8%), NY-ESO-1 (19.4%), MAGE-A3 (19.4%), and TPTE (3.2%). Adult melanomas expressed tyrosinase (86.2%), MAGE-A3 (75.9%), NY-ESO-1 (48.3%), and TPTE (48.3%). Childhood melanocytic nevi only expressed tyrosinase (93.3%). Expression prevalence of individual TAAs did not differ between subtypes of pediatric melanoma, and no association with prognosis was found. All four TAAs were expressed in pediatric melanoma, albeit NY-ESO-1 and MAGE-A3 to a lesser extent than in adult melanoma. These data support the possibility of investigating vaccines targeting these TAAs for the treatment of pediatric melanoma., (© 2024. The Author(s).)

Background: Next-generation sequencing (NGS) is the most commonly used method for determining BRAF mutational status in patients with advanced melanoma. Automated PCR-based methods, such as the Idylla TM system, are increasingly used for mutation diagnostics, but it is unclear what impact the choice of diagnostic method has on the management of melanoma., Objectives: To compare the concordance rate of BRAF V600 mutational analysis using Idylla TM and NGS and to analyze the technical and clinical turnaround time. The clinical relevance is compared by analyzing the impact on the treatment decision., Methods: In this monocentric prospective cohort study, the BRAF mutation status of 51 patients was determined using both methods in parallel., Results: BRAF V600 mutation was detected in 23/51 cases (45%). Idylla TM showed a 100% concordant result with a faster turnaround time (0.2 days) compared to NGS (12.2 days). In general, less tumor material was required for Idylla TM than for NGS. Most patients received immunotherapy as a first-line therapy regardless of the BRAF V600 status., Conclusions: Idylla TM testing proved to be a reliable and rapid alternative to NGS in the determination of BRAF V600 mutation. Although BRAF. status was available earlier, this had no influence on the treatment decision in most cases.

Pediatric melanomas are rare tumors that have clinical and histological differences from adult melanomas. In adult melanoma, the immunohistochemical marker PRAME is increasingly employed as a diagnostic adjunct. PRAME is also under investigation as a target structure for next-generation immunotherapies including T-cell engagers. Little is known about the characteristics of PRAME expression in pediatric melanoma. In this retrospective study, samples from 25 pediatric melanomas were compared with control groups of melanomas in young adults (18-30 years; n = 32), adult melanoma (>30 years, n = 30), and benign melanocytic nevi in children (0-18 years; n = 30) with regard to the immunohistochemical expression of PRAME (diffuse PRAME expression >75%/absolute expression). Pediatric melanomas show lower diffuse PRAME expression (4%) and lower absolute PRAME expression (25%) compared to young adult melanomas (15.6%/46.8%) and adult melanomas (50%/70%). A significant age-dependent expression could be observed. An analysis of event-free survival shows no prognostic role for PRAME in pediatric melanoma and young adult melanoma, but a significant association with diffuse PRAME expression in adulthood. The age dependency of PRAME expression poses a potential pitfall in the diagnostic application of melanocytic tumors in young patients and may limit therapeutic options within this age group. The immunohistochemical expression of the tumor-associated antigen PRAME is an increasingly important diagnostic marker for melanocytic tumors and is gaining attention as a possible immunotherapeutic target in melanoma. As the available data primarily stem from adult melanoma, and given the clinical and histological distinctions in pediatric melanomas, our understanding of PRAME expression in this specific patient group remains limited. The age-dependent low PRAME expression shown here constrains the use of this marker in pediatric melanoma and may also limit the use of immunotherapeutic strategies against PRAME in young patients., (© 2024 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

The majority of patients with Parkinson disease (PD) experience a loss in their sense of smell and accumulate insoluble α-synuclein aggregates in their olfactory bulbs (OB). Subjects affected by a SARS-CoV-2-linked illness (COVID-19) also frequently experience hyposmia. We previously postulated that microglial activation as well as α-synuclein and tau misprocessing can occur during host responses following microbial encounters. Using semiquantitative measurements of immunohistochemical signals, we examined OB and olfactory tract specimens collected serially at autopsies between 2020 and 2023. Deceased subjects comprised 50 adults, which included COVID19 + patients (n = 22), individuals with Lewy body disease (e.g., PD; dementia with Lewy bodies (n = 6)), Alzheimer disease (AD; n = 3), and other neurodegenerative disorders (e.g., progressive supranuclear palsy (n = 2); multisystem atrophy (n = 1)). Further, we included neurologically healthy controls (n = 9), and added subjects with an inflammation-rich brain disorder as neurological controls (NCO; n = 7). When probing for microglial and histiocytic reactivity in the anterior olfactory nuclei (AON) by anti-CD68 immunostaining, scores were consistently elevated in NCO and AD cases. In contrast, microglial signals on average were not significantly altered in COVID19 + patients relative to healthy controls, although anti-CD68 reactivity in their OB and tracts declined with progression in age. Mild-to-moderate increases in phospho-α-synuclein and phospho-tau signals were detected in the AON of tauopathy- and synucleinopathy-afflicted brains, respectively, consistent with mixed pathology, as described by others. Lastly, when both sides were available for comparison in our case series, we saw no asymmetry in the degree of pathology of the left versus right OB and tracts. We concluded from our autopsy series that after a fatal course of COVID-19, microscopic changes in the rostral, intracranial portion of the olfactory circuitry -when present- reflected neurodegenerative processes seen elsewhere in the brain. In general, microglial reactivity correlated best with the degree of Alzheimer's-linked tauopathy and declined with progression of age in COVID19 + patients., (© 2024. The Author(s).)

Background: Histopathologic regression of cutaneous melanoma is considered a favorable prognostic factor, but its significance in clinical practice remains controversial., Objective: To investigate the prognostic importance of regression in patients with primary cutaneous melanoma undergoing sentinel lymph node (SLN) biopsy and to assess its significance in patients progressing to an unresectable stage requiring systemic therapy., Methods: We retrospectively reviewed patients with newly diagnosed melanoma undergoing SLN biopsy between 2010 and 2015 and available information on histopathologic regression (n = 1179). Survival data and associations of clinical variables with SLN status were assessed., Results: Patients with regressive melanoma showed favorable relapse-free (hazard ratio [HR], 0.52; P = .00013), distant metastasis-free (HR, 0.56; P = .0020), and melanoma-specific survival (HR, 0.35; P = .00053). Regression was associated with negative SLN (odds ratio, 0.48; P = .0077). In patients who progressed to an unresectable stage, regression was associated with favorable progression-free survival under immune checkpoint inhibition (HR, 0.43; P = .031) but not under targeted therapy (HR, 1.14; P = .73) or chemotherapy (HR, 3.65; P = .0095)., Limitations: Retrospective, single-institutional design., Conclusions: Regression of cutaneous melanoma is associated with improved prognosis in patients eligible for SLN biopsy as well as in patients with unresectable disease receiving systemic therapy with immune checkpoint inhibitors., Competing Interests: Conflicts of interest Dr Wagner reports advisory board meetings for Pierre Fabre and honoraria and speaker’s fees from Novartis and Sanofi outside the submitted work. Dr Forschner reports honoraria for presentations from BMS, MSD, Novartis, Pierre Fabre; travel support and congress participation support from BMS, Pierre Fabre, Novartis; advisory board participation for MSD, BMS, Novartis, Pierre Fabre, Immunocore; and institutional funding from BMS and Stiftung Immunonkologie outside the submitted work. Dr Leiter has received consultancy fees from MSD, Novartis, and Roche; has participated in advisory board meetings for MSD, Novartis, Sun Pharma, Almirall Hermal, and Roche; has received honoraria from MSD, Novartis, Sun Pharma, Almirall Hermal, and Roche; and has received travel support from Sun Pharma and Pierre Fabre. Dr Amaral reports institutional grants from SkylineDx, institutional grants and personal fees from Novartis, institutional grants from NeraCare, personal fees from BMS, institutional grants from Sanofi, personal fees from CeCaVa, and personal fees from Pierre Fabre, all outside the submitted work. Dr Amaral serves as the current Chair of the ESMO Fellowship Development Committee and was previously the Chair of the ESMO Young Oncologists Committee. Dr Garbe reports personal fees from CeCaVa, personal fees from MSD, personal fees from NeraCare, and personal fees from Philogen, outside the submitted work. Dr Eigentler reports consultant fees from and an advisory role for Philogen, Bristol-Myers Squibb, Novartis, Roche, and Sanofi. Dr Forchhammer reports personal fees from Kyowa Kirin and Recordati Rare Diseases (speaker’s honoraria) as well as institutional grants from NeraCare, SkylineDx, and BioNTech outside the submitted work. Dr Flatz reports grants from the Swiss National Science Foundation, Swiss Cancer League, Hookipa Pharma, and Novartis Foundation outside the submitted work and an advisory role for Novartis and Bristol-Myers Squibb. Ms Knierim and Drs Luttermann, Metzler, Yazdi, Bauer, and Gassenmaier have no conflicts of interest to declare., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The American Joint Committee on Cancer 8th edition (AJCC v8) defines sentinel lymph nodes (SLN) containing any tumor cells as positive SLN. Consequently, even thin melanomas with isolated tumor cells (ic) in SLN are classified as stage IIIA, making them candidates for adjuvant therapy., Objectives and Endpoints: We aimed to evaluate survival outcomes of melanoma stage IIIA (ic) and compare them with stage IIIA with lymph node (LN) metastases > 0.1 mm. Primary endpoints were relapse-free survival (RFS) and distant metastases-free survival (DMFS). Secondary endpoint was melanoma specific survival (MSS)., Results: The discovery cohort from the Department of Dermatology, University Hospital Tuebingen, included 237 patients; confirmation cohort included 143 patients from the DeCOG trial. The Tuebingen cohort included 95 patients with stage IIIA (ic) and 142 patients with stage IIIA. The DeCOG trial included 39 patients with stage IIIA (ic) and 104 patients with stage IIIA. In the Tuebingen cohort, 10-year RFS rates for stage IIIA (ic) and IIIA were 84% (95% CI 75-94) and 49% (95% CI 39-59), respectively (p < 0.001). 10-year DMFS rates for stage IIIA (ic) and IIIA were 89% (95% CI 81-97) and 56% (95% CI 45-67), respectively; (p < 0.001). In the DeCOG cohort, 10-year RFS for stage IIIA (ic) and stage IIIA were 88% (95% CI 78-99) and 35% (95% CI 7-62), respectively; (p = 0.009). 10-year DMFS for stage IIIA (ic) and IIIA was 88% (95% CI 77-99) and 60% (95% CI 39-80), respectively (p = 0.061)., Conclusion: Stage IIIA (ic) melanoma exhibits a prognosis similar to stage IB. Recommendation of adjuvant therapy in Stage IIIA (ic) warrants thorough discussion., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Harnessing the immune system to eradicate tumors requires identification and targeting of tumor antigens, including tumor-specific neoantigens and tumor-associated self-antigens. Tumor-associated antigens are subject to existing immune tolerance, which must be overcome by immunotherapies. Despite many novel immunotherapies reaching clinical trials, inducing self-antigen-specific immune responses remains challenging. Here, we systematically investigate viral-vector-based cancer vaccines encoding a tumor-associated self-antigen (TRP2) for the treatment of established melanomas in preclinical mouse models, alone or in combination with adoptive T cell therapy. We reveal that, unlike foreign antigens, tumor-associated antigens require replication of lymphocytic choriomeningitis virus (LCMV)-based vectors to break tolerance and induce effective antigen-specific CD8 + T cell responses. Immunization with a replicating LCMV vector leads to complete tumor rejection when combined with adoptive TRP2-specific T cell transfer. Importantly, immunization with replicating vectors leads to extended antigen persistence in secondary lymphoid organs, resulting in efficient T cell priming, which renders previously "cold" tumors open to immune infiltration and reprograms the tumor microenvironment to "hot." Our findings have important implications for the design of next-generation immunotherapies targeting solid cancers utilizing viral vectors and adoptive cell transfer., Competing Interests: Declaration of interests C.M.S. is a scientific advisor to, has stock options in, and has received research funding from Enable Medicine, Inc. L.F. is a founder and shareholder of Hookipa Pharma Inc. F.S., S.S., and K.K.O. are employees and stock option holder of Hookipa Pharma, Inc. L.F., S.S.R., S.S., and K.K.O. are listed as inventors of the patent entitled “Arenavirus particles to treat solid tumors” (patent number WO2018/185307 A1) describing the application of artLCMV vectors in the treatment of tumors., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: MEK inhibitors (MEKi) were shown to be clinically insufficiently effective in patients suffering from BRAF wild-type (BRAF WT) melanoma, even if the MAPK pathway was constitutively activated due to mutations in NRAS or NF-1. Thus, novel combinations are needed to increase the efficacy and duration of response to MEKi in BRAF WT melanoma. Disulfiram and its metabolite diethyldithiocarbamate are known to have antitumor effects related to cellular stress, and induction of endoplasmic reticulum (ER) stress was found to synergize with MEK inhibitors in NRAS-mutated melanoma cells. Therefore, we investigated the combination of both therapeutics to test their effects on BRAF-WT melanoma cells and compared them with monotherapy using the MEKi trametinib., Methods: The effects of combined therapy with disulfiram or its metabolite diethyldithiocarbamate and the MEKi trametinib were evaluated in a series of BRAF-WT melanoma cell lines by measuring cell viability and apoptosis induction. Cytotoxicity was additionally assessed in 3D spheroids, ex vivo melanoma slice cultures, and in vivo xenograft mouse models. The response of melanoma cells to treatment was studied at the RNA and protein levels to decipher the mode of action. Intracellular and intratumoral copper measurements were performed to investigate the role of copper ions in the antitumor cytotoxicity of disulfiram and its combination with the MEKi., Results: Diethyldithiocarbamate enhanced trametinib-induced cytotoxicity and apoptosis induction in 2D and 3D melanoma culture models. Mechanistically, copper-dependent induction of oxidative stress and ER stress led to Janus kinase (JNK)-mediated apoptosis in melanoma cells. This mechanism was also detectable in patient-derived xenograft melanoma models and resulted in a significantly improved therapeutic effect compared to monotherapy with the MEKi trametinib., Conclusions: Disulfiram and its metabolite represent an attractive pharmaceutical approach to induce ER stress in melanoma cells that potentiates the antitumor effect of MEK inhibition and may be an interesting candidate for combination therapy of BRAF WT melanoma., (© 2024. The Author(s).)

Purpose: Since the introduction of immune checkpoint inhibitors (ICI) and targeted therapies (TT), survival rates of metastatic melanoma patients have increased significantly and complete remissions are no longer rarities. Consequently, there is an increasing number of long-term survivors who have not yet been comprehensively characterized., Methods: We included melanoma patients who entered stage IV between 2014 and 2017 and survived at least 5 years after entering stage IV. Descriptive statistics were performed to characterize the applied systemic therapies, response rates and to report which of these patients are still alive today., Results: 640 patients entered stage IV at the University Hospital Tuebingen. Of these, 207 patients (32%) were still alive at least 5 years after entering stage IV. Details of applied therapies and response rates were available in 176 patients (85%). About 90% of patients (n = 159) were still alive at the time of analysis. Median survival since first stage IV diagnosis was 6.0 years (range 5-9 years). An impressive majority of patients (n = 146, 83%) were no longer receiving systemic therapy at the time of evaluation. Complete remission under first line systemic therapy was seen in 36% of the patients., Conclusion: This dataset comprises the largest available cohort of long-term surviving stage IV melanoma patients. Since 90% of patients in our cohort are still alive today, we expect an increasing number of long-term survivors in the future. Our data indicate the need for specific follow-up programs addressing the needs of long-term survivors., (© 2024. The Author(s).)

Background: Targeted therapy (TT) of BRAF V600 mutated unresectable melanoma with inhibitors of the MAPK pathway achieves response rates of up to 76%, but most patients develop secondary resistance. Albeit TT is strikingly efficacious during the first days of treatment, even in advanced cases, long-term survival is highly unlikely, especially in patients with unfavorable baseline characteristics like elevated lactate dehydrogenase (LDH). In patients treated with anti-PD-1 immune checkpoint inhibitors, elevated baseline metastatic growth rate (MGR) was the most important prognostic factor. Here, we aimed at investigating the prognostic impact of MGR in patients with unresectable melanoma receiving TT., Methods: Clinical records of 242 patients with at least one measurable target lesion (TL) receiving TT at seven skin cancer centers were reviewed. Baseline MGR was determined measuring the largest TL at baseline and at one earlier timepoint., Results: Overall survival (OS) and progression-free survival (PFS) were significantly impaired in patients with an MGR > 3.9 mm/month (median OS: 11.4 vs. 35.5 months, P < 0.0001; median PFS: 4.8 vs. 9.2 months, P < 0.0001). Multivariable analysis of OS and PFS revealed that the prognostic impact of elevated MGR was independent of LDH, presence of brain and liver metastases, tumor burden, and line of treatment. The prognostic significance of elevated MGR was highest in patients with normal LDH., Conclusions: Baseline MGR is an important independent prognostic marker for OS and PFS in melanoma patients treated with TT. Its implementation in clinical routine is easy and could facilitate the prognostic stratification., Competing Interests: Declaration of Competing Interest N.B.W. has participated in advisory board meetings for Novartis, Pierre Fabre, and Sanofi, and received speaker fees from Sanofi, outside the submitted work. A.Oe. has received consultant fees from MSD and Bristol-Myers Squibb; has participated in advisory board meetings for MSD and Bristol-Myers Squibb. T.A. received institutional grants from SkylineDx, Neracare, Novartis, Sanofi, and consulting fees from Novartis, Neracare, BMS, CeCaVa and Chemosat, outside the submitted work. A.F. served as a consultant to Novartis, MSD, BMS, Pierre-Fabre and Immunocore; received travel support from Novartis, BMS, Pierre-Fabre, and received speaker fees from Novartis, BMS and MSD and reports institutional research grants from BMS Stiftung Immunonkologie, outside the submitted work. U.L. has received consultancy fees from MSD, Novartis, and Roche; has participated in advisory board meetings for MSD, Novartis, and Roche; has received honoraria from MSD, Novartis, and Roche. P.T. has received honoraria and/or consultancy fees from Bristol-Myers Squibb, Curevac, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi; has received travel support from Bristol-Myers Squibb and Pierre-Fabre. J.M. has received consultancy fees from Merck/Pfizer, MSD, Amgen, Novartis, Bristol-Myers Squibb, and Pierre Fabre; has participated in advisory board meetings for Merck/Pfizer, MSD, Amgen, Novartis, Bristol-Myers Squibb, and Pierre Fabre; has received travel support from Ultrasun, L′Oreal, MSD, Bristol-Myers Squibb, and Pierre Fabre. C.L. has received consultancy fees from, has participated in advisory board meetings for, has received speaker’s fees, and/or has received travel reimbursements from Roche, Pierre Fabre, Novartis, Bristol-Myers Squibb, Merck, MSD, Biontech, Almiral Hermal, Kyowa Kirin, Sun Pharma and Sanofi. C.G. has received personal fees from CeCaVa, MSD, NeraCare and Philogen. F.M. has received speaker’s fees from, has received travel support from, and has participated in advisory board meeting for Novartis, Roche, Bristol-Myers Squibb, MSD and Pierre Fabre; has received research funding from Novartis and Roche. T.K.E. has received consultancy fees from Philogen, Bristol-Myers Squibb, Novartis, Roche, Merck, and Sanofi; has participated in advisory board meetings for CureVac, Philogen, Bristol-Myers Squibb, Novartis, Roche, and Sanofi. L.F. has received grant funding from the Swiss National Science Foundation, Swiss Cancer League, Hookipa Pharma and Novartis Foundation; has participated in advisory board meetings for Novartis and Bristol-Myers Squibb. M.M.L., K.K., L.R., M.F., N.R., R.S., C.Z., C.E., S.K., B.K., W.H., and A.C. have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Ltd.)

Immune checkpoint inhibitors have revolutionized cancer therapy, yet the efficacy of these treatments is often limited by the heterogeneous and hypoxic tumor microenvironment (TME) of solid tumors. In the TME, programmed death-ligand 1 (PD-L1) expression on cancer cells is mainly regulated by Interferon-gamma (IFN-γ), which induces T cell exhaustion and enables tumor immune evasion. In this study, we demonstrate that acidosis, a common characteristic of solid tumors, significantly increases IFN-γ-induced PD-L1 expression on aggressive cancer cells, thus promoting immune escape. Using preclinical models, we found that acidosis enhances the genomic expression and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and the translation of STAT1 mRNA by eukaryotic initiation factor 4F (elF4F), resulting in an increased PD-L1 expression. We observed this effect in murine and human anti-PD-L1-responsive tumor cell lines, but not in anti-PD-L1-nonresponsive tumor cell lines. In vivo studies fully validated our in vitro findings and revealed that neutralizing the acidic extracellular tumor pH by sodium bicarbonate treatment suppresses IFN-γ-induced PD-L1 expression and promotes immune cell infiltration in responsive tumors and thus reduces tumor growth. However, this effect was not observed in anti-PD-L1-nonresponsive tumors. In vivo experiments in tumor-bearing IFN-γ -/- mice validated the dependency on immune cell-derived IFN-γ for acidosis-mediated cancer cell PD-L1 induction and tumor immune escape. Thus, acidosis and IFN-γ-induced elevation of PD-L1 expression on cancer cells represent a previously unknown immune escape mechanism that may serve as a novel biomarker for anti-PD-L1/PD-1 treatment response. These findings have important implications for the development of new strategies to enhance the efficacy of immunotherapy in cancer patients., (© 2023. The Author(s).)

Introduction: Combined immune checkpoint inhibition (ICI) with ipilimumab and nivolumab is a widely used treatment regimen for metastatic melanoma with non-resectable metastases. Nevertheless, the standard dose of ipilimumab 3 mg/kg bw and nivolumab 1 mg/kg bw is associated with a high rate of treatment-related adverse events (trAEs) (59% grade 3-4). In the CheckMate 511 study, it could be shown that flipped dosing with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw resulted in a significant reduction of trAE., Methods: We have also used this regimen in the clinical setting and report the trAE, progression-free survival, and overall survival for 79 patients with metastatic melanoma who started combined ICI in the flipped dosing between March 2019 and April 2020., Results: in total, 40 patients started first-line, 50% of whom had an elevated lactate dehydrogenase level at baseline. The disease control rate of these patients was 50%. The 2-year overall survival rate 67%. Moreover, 33% of the patients suffered grade 3 or 4 treatment related adverse events., Discussion: The results of our study correspond very well to the results of the CheckMate 511 study (2-year OS: 65%, grade 3-4 immune-related side effects: 35%). Combined ICI with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw seems to be an equally effective but better-tolerated therapy regimen for metastasized melanoma patients, also in a real-world cohort., Competing Interests: TA reports institutional funding from SkylineDx B.V. in relation to the submitted work. TA reports personal honoraria from BMS, CeCaVa, Novartis and Pierre-Fabre; Institutional financial support from iFIT, Neracare, Novartis and Sanofi and institutional research Grant from Novartis, outside the submitted work. UL reports research support from MSD, consulting fees and honoraria from Sun Pharma, Sanofi personal and institutional, MSD personal and institutional, Novartis, Roche, Almirall Hermal, support for attending meeting from Sun Pharma and participation on a Data Safety Monitoring Board or Advisory Board from Sun Pharma, Sanofi, MSD, Novartis, Roche, Almirall Hermal, outside the submitted work. LF reports Grants or contracts from Hookipa Pharma, SAKK/Immunophotonics, DFG Grant Deutsche Forschungsgemeinschaft, Philogen and Mundipharma; consulting fees from Philogen, Sanofi, Novartis, BMS; participation on Data Safety Board University of Basel and stocks or stock options from Hookipa Pharma, outside the submitted work. AF reports honoraria for presentations for BMS, MSD, Novartis, Pierre-Fabre; Travel support and congress participation support from BMS, Pierre-Fabre, Novartis; Advisory Boards from MSD, BMS, Novartis, Pierre-Fabre, Immunocore and institutional funding from BMS Stiftung Immunonkologie, outside the submitted work. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nübel, Amaral, Leiter, Flatz and Forschner.)

Background: The role of autoreactive T cells on the course of Coronavirus disease-19 (COVID-19) remains elusive. Type II pneumocytes represent the main target cells of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Autoimmune responses against antigens highly expressed in type II pneumocytes may influence the severity of COVID-19 disease., Objective: The aim of this study was to investigate autoreactive T cell responses against self-antigens highly expressed in type II pneumocytes in the blood of COVID-19 patients with severe and non-severe disease., Methods: We collected blood samples of COVID-19 patients with varying degrees of disease severity and of pre-pandemic controls. T cell stimulation assays with peptide pools of type II pneumocyte antigens were performed in two independent cohorts to analyze the autoimmune T cell responses in patients with non-severe and severe COVID-19 disease. Target cell lysis assays were performed with lung cancer cell lines to determine the extent of cell killing by type II PAA-specific T cells., Results: We identified autoreactive T cell responses against four recently described self-antigens highly expressed in type II pneumocytes, known as surfactant protein A, surfactant protein B, surfactant protein C and napsin A, in the blood of COVID-19 patients. These antigens were termed type II pneumocyte-associated antigens (type II PAAs). We found that patients with non-severe COVID-19 disease showed a significantly higher frequency of type II PAA-specific autoreactive T cells in the blood when compared to severely ill patients. The presence of high frequencies of type II PAA-specific T cells in the blood of non-severe COVID-19 patients was independent of their age. We also found that napsin A-specific T cells from convalescent COVID-19 patients could kill lung cancer cells, demonstrating the functional and cytotoxic role of these T cells., Conclusions: Our data suggest that autoreactive type II PAA-specific T cells have a protective role in SARS-CoV-2 infections and the presence of high frequencies of these autoreactive T cells indicates effective viral control in COVID-19 patients. Type II-PAA-specific T cells may therefore promote the killing of infected type II pneumocytes and viral clearance., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: Conflicts of interest Dr Amaral reports personal honoraria from BMS, CeCaVa, Novartis, and Pierre Fabre, institutional financial support from iFIT, NeraCare, Novartis, Sanofi, and SkylineDx, and institutional research grants from Novartis, outside the submitted work. Drs Sinnberg and Niessner report institutional funding from Novartis and Pierre Fabre outside the submitted work. Dr Ring listed as inventors of the patent entitled “Arenavirus particles to treat solid tumors” (patent number WO2018/185307 A1) describing the application of artLCMV vectors in the treatment of tumors, outside the submitted work. Dr Joerger reports advisory role (institutional): Novartis, AstraZeneca, Basilea Pharmaceutica, Bayer, BMS, Debiopharm, MSD, Roche, and Sanofi, research funding: Swiss Cancer Research, and travel grants: Roche, Sanofi, and Takeda. Dr Schroeder reports institutional grants from Illumina and research grants from BMS Stiftung Immunonkologie outside the submitted work. Dr Cozzio has served as adviser for and/or received speaking fees from AbbVie, Almirall, Amgen, BMS, Eli Lilly, Galderma, LEO Pharma, Janssen-Cilag, Novartis, Pfizer, Pierre Fabre Pharma, Sanofi, and UCB, outside the submitted work. Dr Leiter reports research support from MSD, consulting fees and honoraria from Sun Pharma, Sanofi (personal and institutional), MSD (personal and institutional), Novartis, Roche, and Almirall Hermal, support for attending meeting from Sun Pharma and participation on a Data Safety Monitoring Board or Advisory Board from Sun Pharma, Sanofi, MSD, Novartis, Roche, and Almirall Hermal, outside the submitted work. Dr Thomas reports honoraria for talks or advisory boards from BMS and Pierre Fabre and also reports research funding (institutional) from BMS, Pfizer, MSD, Amgen, argenx, LEO, Novartis, UCB, 4SC, AstraZeneca, BioNtech, Genentech, Roche, Biotech, CureVac, HUYA, Incyte, Idera, Iovance, InflaRx, CerpassRx, Kartos, Nektar, Philogen, Pierre Fabre, Regeneron, Replimune, and Sanofi. Dr Garbe reports personal fees from Amgen, MSD, and Philogen and grants and personal fees from Novartis, NeraCare, BMS, Roche, and Sanofi, outside the submitted work. Dr Forchhammer received personal fees from Recordati, Kyowa Kirin, and Takeda Pharmaceuticals (speakers’ honoraria) as well as institutional grants from NeraCare, SkylineDx, and BioNTech outside the submitted work. Dr Levesque has received project-specific research funding outside the scope of this work from Novartis, Roche, Molecular Partners, and Oncobit. Dr Mangana has intermittent projects focused consultancy or advisory relationships with Merck/Pfizer, MSD, Amgen, Novartis, Roche, BMS, and Pierre Fabre and has received travel support from Ultrasun, L’Oreal, MSD, BMS, and Pierre Fabre outside of the submitted work. Dr Dummer reports research funding to their institution for clinical studies from MSD and consulting or advisory roles with MSD, Novartis, Roche, BMS, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX, Pfizer, and touchIME outside the submitted work. Dr Schürch is on the Scientific Advisory Board of and has received research funding from Enable Medicine, Inc, both outside the current work. Dr Forschner served as consultant to Roche, Novartis, MSD, BMS, and Pierre Fabre, received travel support from Roche, Novartis, BMS, and Pierre Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT and also reports institutional research grants from BMS Stiftung Immunonkologie. Dr Flatz reports grants or contracts from Hookipa Pharma, SAKK/Immunophotonics, DFG grant (Deutsche Forschungsgemeinschaft), Philogen, and Mundipharma, consulting fees from Philogen, Sanofi, Novartis, and BMS, participation on Data Safety Board University of Basel, outside the submitted work. The other authors have no conflicts of interest to declare.

The increasing number of melanoma patients makes it necessary to develop best possible strategies for prognosis assessment in order to recommend appropriate therapy and follow-up. The prognostic significance of tumor cell pigmentation has not been fully elucidated. Hematoxylin and eosin (H&E)-stained sections of 775 melanomas diagnosed between 2012 and 2015 were independently assessed for melanin pigment abundance by two investigators, and the impact on melanoma-specific survival was calculated. Unpigmented melanomas (n = 99) had a melanoma-specific survival of 67.7%, melanomas with moderate pigmentation (n = 384) had a melanoma-specific survival of 85.9%, and strongly pigmented melanomas (n = 292) had a melanoma-specific survival of 91.4% (p < .001). In an analysis of melanoma-specific survival adjusted for pT stage and pigmentation, we found a nonsignificant impact of pigmentation abundance with a hazard ratio of 1.277 (p = .74). The study presented here provides evidence in a German cohort that patients with pigmented melanomas have a more favorable prognosis than those diagnosed with nonpigmented melanomas. Moreover, the abundance of pigmentation already seems to provide a first prognostic estimate. However, it does not appear to provide significant additional value for prognostic assessment according to the AJCC 2017 pT classification., (© 2023 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Background and Objectives: The melanoma guideline is mainly based on the AJCC stage. There is no difference according to histological subtypes such as superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM) or nodular malignant melanoma (NM). We aimed to evaluate whether patients with LMM have a different clinical course from patients with SSM/NM. This is particularly important as adjuvant anti-PD-1 therapy is approved for stage IIB and IIC melanoma., Patients and Methods: Data were extracted from the Central Registry of Malignant Melanoma. Only patients with LMM, SSM, and NM of the head and neck with primary diagnosis between 01/01/2000 and 12/31/2019 were included. Progression-free survival (PFS), melanoma-specific survival (MSS), and pattern of metastases were analyzed for the LMM group compared to SSM/NM., Results: The LMM cohort (n = 902) had significantly better MSS than the SSM/NM cohort (n = 604). There was no difference in PFS. The 5-year MSS of the stage II LMM cohort was 88.5% (95% CI 81.4-95.6) compared to 79.7% (95% CI 72.8-86.6) in the stage II SSM/NM cohort., Conclusion: It does not appear appropriate to use adjuvant therapy in stage II LMM patients to the same extent as in patients with SSM/NM., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, their use is frequently associated with immune-related adverse events (irAEs) potentially affecting any organ. The mechanisms mediating such irAEs remain poorly understood and biomarkers to predict the development of irAEs are lacking. Growing evidence shows the importance of self-antigens in mediating irAEs during ICI therapy, in particular the well-described melanocyte differentiation antigens in melanoma patients. This review will focus on two novel classes of self-antigens involved in mediating autoimmune skin toxicity and pneumonitis in non-small cell lung cancer patients treated with immunotherapy. T cells specific for these self-antigens are thought to not only mediate irAEs but are thought to simultaneously mediate anti-tumor responses and are therefore associated with both autoimmune toxicity and response to ICI therapy. We further discuss emerging cellular and proteomic immune signatures of irAEs that may serve as biomarkers to help predict which patients are at higher risk of developing these irAEs. The determination of new tumor antigens involved in ICI therapy and the identification of related biomarkers brings us a step forward in the mechanistic understanding of ICIs and will help to monitor patients at higher risk of developing irAEs. Lastly, we discuss the current challenges in collecting research samples for the study of ICI-related mechanisms and in distinguishing between immune signatures of response and those of irAEs., (© 2023 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.)

Recent studies suggest that BRAF V600 -mutated melanomas in particular respond to dual anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibition (ICI). Here we identified an over-representation of interleukin (IL)-17-type 17 helper T (T H 17) gene expression signatures (GES) in BRAF V600 -mutated tumors. Moreover, high baseline IL-17 GES consistently predicted clinical responses in dual-ICI-treated patient cohorts but not in mono anti-CTLA-4 or anti-PD-1 ICI cohorts. High IL-17 GES corresponded to tumor infiltration with T cells and neutrophils. Accordingly, high neutrophil infiltration correlated with clinical response specifically to dual ICI, and tumor-associated neutrophils also showed strong IL-17-T H 17 pathway activity and T cell activation capacity. Both the blockade of IL-17A and the depletion of neutrophils impaired dual-ICI response and decreased T cell activation. Finally, high IL-17A levels in the blood of patients with melanoma indicated a higher global T H 17 cytokine profile preceding clinical response to dual ICI but not to anti-PD-1 monotherapy, suggesting a future role as a biomarker for patient stratification., (© 2023. The Author(s).)

Background: Recent advances in digital pathology have enabled accurate and standardised enumeration of tumour-infiltrating lymphocytes (TILs). Here, we aim to evaluate TILs as a percentage electronic TIL score (eTILs) and investigate its prognostic and predictive relevance in cutaneous melanoma., Methods: We included stage I to IV cutaneous melanoma patients and used hematoxylin-eosin-stained slides for TIL analysis. We assessed eTILs as a continuous and categorical variable using the published cut-off of 16.6% and applied Cox regression models to evaluate associations of eTILs with relapse-free, distant metastasis-free, and overall survival. We compared eTILs of the primaries with matched metastasis. Moreover, we assessed the predictive relevance of eTILs in therapy-naïve metastases according to the first-line therapy., Findings: We analysed 321 primary cutaneous melanomas and 191 metastatic samples. In simple Cox regression, tumour thickness (p < 0.0001), presence of ulceration (p = 0.0001) and eTILs ≤16.6% (p = 0.0012) were found to be significant unfavourable prognostic factors for RFS. In multiple Cox regression, eTILs ≤16.6% (p = 0.0161) remained significant and downgraded the current staging. Lower eTILs in the primary tissue was associated with unfavourable relapse-free (p = 0.0014) and distant metastasis-free survival (p = 0.0056). In multiple Cox regression adjusted for tumour thickness and ulceration, eTILs as continuous remained significant (p = 0.019). When comparing TILs in primary tissue and corresponding metastasis of the same patient, eTILs in metastases was lower than in primary melanomas (p < 0.0001). In therapy-naïve metastases, an eTILs >12.2% was associated with longer progression-free survival (p = 0.037) and melanoma-specific survival (p = 0.0038) in patients treated with anti-PD-1-based immunotherapy. In multiple Cox regression, lactate dehydrogenase (p < 0.0001) and eTILs ≤12.2% (p = 0.0130) were significantly associated with unfavourable melanoma-specific survival., Interpretation: Assessment of TILs is prognostic in primary melanoma samples, and the eTILs complements staging. In therapy-naïve metastases, eTILs ≤12.2% is predictive of unfavourable survival outcomes in patients receiving anti-PD-1-based therapy., Funding: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript., Competing Interests: Declaration of interests SF received personal fees from Kyowa Kirin and Takeda Pharmaceuticals, institutional grants from NeraCare, SkylineDx, and BioNTech, all outside the submitted work. TA reports institutional grants and personal fees from Novartis, institutional grants from NeraCare, Sanofi, SkylineDx, personal fees from CeCaVa, Pierre Fabre, BMS all outside the submitted work, participate on a data safety monitoring board for Unicancer. DLR reports grants and personal fees from Amgen, Astra Zeneca, Cepheid, Konica—Minolta, Lilly, NextCure personal fees from Cell Signaling Technology, Danaher, Fluidigm, GSK, Merck, Monopteros, NanoString, Odonate, Paige. AI, Regeneron, Roche, Sanofi, Ventana and Verily, royalties from Rarecyte, all outside the submitted work. CG reports grants and personal fees from NeraCare, Novartis, Roche, Sanofi, personal fees from Amgen, BMS, MSD, and Philogen, all outside the submitted work. TE reports personal fees from Novartis, BMS, Almirall Hermal, CureVac, Sanofi, MSD, Pierre Fabre and institutional grants from MSD, Sanofi, BMS, Pfizer, GenenTech, Seagan, Regeneron all outside the submitted work. IB reports having received speaker fees from Bayer, Pfizer, Takeda and AstraZeneca. MR reports grants from AB Science, Abbott, AbbVie, Alcedis, Almirall Hermal, Amgen, Anaptys Bio, Argenx, AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, CureVac, DelArrivo, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Dynavax Tech, Eli Lilly, Galderma, Genentech, GSK, Hoffmann La Roche, Hokusai, Idera Pharmaceuticals, Ilkos Therapeutic, Immatics biotechnologies, Incyte, Iovance Biotherapeutics, Janssen Cilag, Johnson & Johnson, LEO Pharma, Merck, MSD Sharp &Dohme, Novartis Pharmaceuticals, PellePharm, Pfizer, Philogen, Regeneron Pharmaceuticals, Sanofi Aventis, Schering Plough, Sun Pharma, Technische Universitat Dresden, Topaz Therapeutics, UCB, Universitatsklinik Essen, Universitatklinik Koln, Wilhelm Sander-Stiftung, 4SC. The other authors report no potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Immune checkpoint inhibition (ICI) has changed the melanoma treatment spectrum. Few studies have examined the characteristics and long-term outcomes of patients achieving complete response (CR) under ICI., Materials and Methods: We evaluated patients with unresectable stage IV melanoma treated with first-line ICI. The characteristics of those achieving CR were compared with those not achieving CR. Progression-free survival (PFS) and overall survival (OS) were assessed. Late-onset toxicities, response to second-line treatment, the prognostic value of clinicopathologic features, and blood markers were examined., Results: A total of 265 patients were included; 41 (15.5%) achieved CR, while 224 (84.5%) had progressive disease, stable disease, or partial response. At the therapy start, those who had CR were more likely to be older than 65 years of age (p = 0.013), have a platelet-to-lymphocyte ratio below 213 (p = 0.036), and have lower lactate dehydrogenase levels (p = 0.008) than those not achieving a CR. For those who discontinued therapy after CR, the median follow-up time after CR was 56 months (interquartile range [IQR] 52-58) and the median time from CR to therapy end was 10 months (IQR 1-17). Five-year PFS after CR was 79% and 5-year OS was 83%. Most complete responders had a normalization of S100 at the time of CR (p < 0.001). In simple Cox regression analysis, age below 77 years at CR (p = 0.04) was associated with better prognosis after CR. Eight patients received second-line ICI; disease control was seen in 63%. Late immune-related toxicities occurred in 25% of patients, most being cutaneous immune-related toxicities., Conclusions: Response, according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, is, until now, the most important prognostic factor, and CR is a valid surrogate marker for long-term survival in patients treated with ICI. Our results highlight the importance of investigating the optimal therapy duration in complete responders., (© 2023. The Author(s).)

Background: The COVID-19 lockdown had a dramatic impact on primary care access and resulted in postponed skin cancer screenings. This raises concerns for a diagnostic delay on primary cutaneous melanomas, which can subsequently increase morbidity and mortality., Objectives: The aim of the study was to investigate the impact of the COVID-19-related restrictions on the melanoma diagnosis in five European skin cancer reference centres in Switzerland, Germany, Austria and Italy., Methods: A total of 7865 cutaneous melanoma cases were collected between 01 September 2018 and 31 August 2021. The time period was stratified into pre-COVID (pre-lockdown) and post-COVID (lockdown and post-lockdown) according to the established restrictions in each country. The data collection included demographic, clinical and histopathological data from histologically confirmed cutaneous melanomas. Personal and family history of melanoma, and presence of immunosuppression were used to assess the diagnosis delay in high-risk individuals., Results: There was an overall increase of the Breslow tumour thickness (mean 1.25 mm vs. 1.02 mm) during the post-COVID period, as well as an increase in the proportion of T3-T4 melanomas, rates of ulceration and the number of mitotic rates ≥2 (all, p < 0.001). Patients with immunosuppression and personal history of melanoma showed a decrease in the mean log10-transformed Breslow during lockdown and post-COVID. In the multivariate analysis, age at melanoma diagnosis (p < 0.01) and personal history of melanoma (p < 0.01) showed significant differences in the mean Breslow thickness., Conclusions: The study confirms the diagnostic delay in cutaneous melanomas due to the COVID-19 lockdown. High-risk individuals, such as patients with personal history of melanoma and elderly individuals, were more hesitant to restart their regular skin cancer screenings post-COVID. Further studies with longer follow-up are required to evaluate the consequences of this diagnostic delay in long-term outcomes., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Aim/Introduction: Despite the spectacular success of immune checkpoint inhibitor therapy (ICT) in patients with metastatic cancer, only a limited proportion of patients benefit from ICT. CD8 + cytotoxic T cells are important gatekeepers for the therapeutic response to ICT and are able to recognize MHC class I-dependent tumor antigens and destroy tumor cells. The radiolabeled minibody [ 89 Zr]Zr-Df-IAB22M2C has a high affinity for human CD8 + T cells and was successfully tested in a phase I study. Here, we aimed to gain the first clinical PET/MRI experience with the noninvasive assessment of the CD8 + T-cell distribution in cancer patients by in vivo [ 89 Zr]Zr-Df-IAB22M2C with a distinct focus of identifying potential signatures of successful ICT. Material and Methods: We investigated 8 patients with metastasized cancers undergoing ICT. Radiolabeling of Df-IAB22M2C with Zr-89 was performed according to Good Manufacturing Practice. Multiparametric PET/MRI was acquired 24 h after injection of 74.2±17.9 MBq [ 89 Zr]Zr-Df-IAB22M2C. We analyzed [ 89 Zr]Zr-Df-IAB22M2C uptake within the metastases and within primary and secondary lymphatic organs. Results: [ 89 Zr]Zr-Df-IAB22M2C injection was tolerated well without noticeable side effects. The CD8 PET/MRI data acquisitions 24 hours post-administration of [ 89 Zr]Zr-Df-IAB22M2C revealed good image quality with a relatively low background signal due to only low unspecific tissue uptake and marginal blood pool retention. Only two metastatic lesions showed markedly increased tracer uptake in our cohort of patients. Furthermore, we observed high interpatient variability in [ 89 Zr]Zr-Df-IAB22M2C uptake within the primary and secondary lymphoid organs. Four out of five ICT patients exhibited rather high [ 89 Zr]Zr-Df-IAB22M2C uptake in the bone marrow. Two of these four patients as well as two other patients yielded pronounced [ 89 Zr]Zr-Df-IAB22M2C uptake within nonmetastatic lymph nodes. Interestingly, cancer progression in ICT patients was associated with a relatively low [ 89 Zr]Zr-Df-IAB22M2C uptake in the spleen compared to the liver in 4 out of the 6 patients. Lymph nodes with enhanced [ 89 Zr]Zr-Df-IAB22M2C uptake revealed significantly reduced apparent diffusion coefficient (ADC) values in diffusion weighted MRI. Conclusion: Our first clinical experiences revealed the feasibility of [ 89 Zr]Zr-Df-IAB22M2C PET/MRI in assessing potential immune-related changes in metastases and primary and secondary lymphatic organs. According to our results, we hypothesize that alterations in [ 89 Zr]Zr-Df-IAB22M2C uptake in primary and secondary lymphoid organs might be associated with the response to ICT., Competing Interests: Competing Interests: R.K. and I.W. are employees of ImaginAB. ClF is an advisor of ImaginAB. The other authors report no conflicts of interest., (© The author(s).)

Purpose: Patients with cutaneous melanoma stage I/IIA disease are currently not eligible for adjuvant therapy, despite their risk for relapses and death. This study validates the ability of a model combining clinicopathologic factors with gene expression profiling (CP-GEP) to identify patients at high risk for disease recurrence in stage I/II and subgroup stage I/IIA., Patients and Methods: 543 patients with stage I/II primary cutaneous melanoma from the University of Tuebingen diagnosed between 2000 and 2017 were analysed. All patients received sentinel lymph node biopsy (SLNB). Analysis was conducted for a separate group of 80 patients who did not undergo SLNB., Results: CP-GEP stratified 424 stage I/IIA patients (78% of the cohort) according to their risk for recurrence, with five-year relapse-free survival (RFS) rates of 77.8% and 93% for CP-GEP high risk (195 patients) and low risk (229 patients), respectively, and hazard ratio of 3.53 (p-value <0.001). In patients who did not receive SLNB biopsy, CP-GEP captured 6 out of 7 relapses., Conclusion: CP-GEP can be used to identify primary cutaneous melanoma patients with a high risk for disease recurrence - especially for stage I/IIA, who are considered low risk by AJCC 8th. These patients may benefit from adjuvant therapy. Also, in the future, when SLNB may become irrelevant, CP-GEP may serve as a risk stratification tool., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TA reports institutional funding from SkylineDx B.V. in relation to the submitted work. Dr. TA reports personal honoraria from BMS, CeCaVa, Novartis and Pierre-Fabre; Institutional financial support from iFIT, Neracare, Novartis and Sanofi and institutional research Grant from Novartis, outside the submitted work. TS reports institutional funding from Novartis and Pierre-Fabre outside the submitted work. EC reports no relationships to disclose. HN reports institutional funding from Novartis and Pierre-Fabre outside the submitted work. UL reports research support from MSD, consulting fees and honoraria from Sun Pharma, Sanofi (personal and institutional), MSD (personal and institutional), Novartis, Roche, Almirall Hermal, support for attending meeting from Sun Pharma and participation on a Data Safety Monitoring Board or Advisory Board from Sun Pharma, Sanofi, MSD, Novartis, Roche, Almirall Hermal, outside the submitted work. UK reports no relationships to disclose. AF reports honoraria for presentations for BMS, MSD, Novartis, Pierre-Fabre; Travel support and congress participation support from BMS, Pierre-Fabre, Novartis; Advisory Boards from MSD, BMS, Novartis, Pierre-Fabre, Immunocore and institutional funding from BMS Stiftung Immunonkologie, outside the submitted work. JD reports stock and other ownership interests – SkylineDx B.V., Employment – SkylineDx B.V.; Leadership – SkylineDx B.V. and Honoraria – SciBase A.B. FTF reports stock and other ownership interests – SkylineDx B.V., Employment – SkylineDx B.V. RW reports stock and other ownership interests – SkylineDx B.V., Employment – SkylineDx B.V. LF reports Grants or contracts from Hookipa Pharma, SAKK/Immunophotonics, DFG Grant (Deutsche Forschungsgemeinschaft), Philogen and Mundipharma; consulting fees from Philogen, Sanofi, Novartis, BMS; participation on Data Safety Board University of Basel and stocks or stock options from Hookipa Pharma, outside the submitted work. AE reports stock and other ownership interests - IO Biotech, Sairopa, SkylineDx B.V.; Honoraria – BMS; Merck/MSD Consulting or Advisory Role - Agenus, BioInvent, Brenus, CatalYm, Clover Pharmaceuticals, Ellipses, Galecto, GSK, IO Biotech, Immunicum, ISA Pharmaceuticals, Merck, MSD, Sairopa, Sellas, SkylineDx B.V., TigaTx, Trained Therapeutics; Data safety monitoring board: Biocad, BioNTech, GSK, Pfizer; Advisory board: BioInvent, CatalYm, GSK, IO Biotech, Merck. SF reports institutional funding from SkylineDx B.V. in relation to the submitted work. Dr. SFalso reports institutional Grants/Contracts from Biontech and Neracare and personal honoraria for lectures from Recordati and KyowaKirin, outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs., Methods: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs., Findings: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67 + regulatory T cells (Tregs) and Ki-67 + CD8 + T cells is also likely to be associated with increased risk of irAEs., Conclusions: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs., Funding: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen., Competing Interests: Declaration of interests L.F. has/had advisory roles for Novartis, Sanofi, Philogen, and Bristol-Myers Squibb, all which took place outside the submitted work. P.A.A. has/had consultant/advisory roles for Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Takis, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, Bio-Al Health, and ValoTx; he also received research funding from Bristol-Myers Squibb, Roche-Genentech, Array, Sanofi, and Pfizer, as well as travel support from Merck Sharp & Dhome and Pfizer, all which was outside the submitted work. T.A. served as consultant to Bristol-Myers Squibb, Novartis, and CeCaVa; received travel support from Bristol-Myers Squibb and Novartis; received speaker fees from Novartis, Bristol-Myers Squibb, Pierre Fabre, and CeCaVa; received institutional funding from Neracare, Novartis, Sanofi, and SkylineDX; and received institutional research grants from Novartis outside the submitted work. R.D. has intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, and touchIME, all which took place outside the submitted work. W.v.d.V. declares research support from the Novartis research foundation and the PROMEDICA Stiftung and serves as a consultant for Mabylon outside the submitted work. S.U. declares research support from Bristol-Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis, and Roche; and travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre outside the submitted work. L.Z. declares speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Sunpharma; research support from Novartis; and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma, and Novartis outside the submitted work. F.D. receives/received honoraria and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, and Sun Pharma outside the submitted work. L.H. declares research support from Therakos and speakers and advisory board honoraria from Amgen, BiomeDx, Bristol-Myers Squibb, Curevac, Merck, Merck Sharp & Dohme, Myoncare, Novartis, Pierre Fabre, Sanofi, SUN, and Roche, outside the submitted work. M.E. declares honoraria and travel support from Bristol-Myers Squibb, Immunocore, and Novartis outside the submitted work. R.K. declares travel support from Pierre Fabre and Sun Pharma outside the submitted work. M.J. declares advisory roles (institutional) for Novartis, AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol-Myers Squibb, Debiopharm, Merck Sharp & Dhome, Roche, and Sanofi; research funding from Swiss Cancer Research; and travel grants from Roche, Sanofi, and Takeda. D.S. has/had consultant/advisory roles in the last 3 years for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Array, Merck Serono, Pfizer, Pierre Fabre, Sun Pharma, Sanofi, Regeneron, Ultimovacs, Sandoz, Immunocore, 4SC, Neracare, Nektar, Daiichi Sankyo, Oncosec, Amgen, BioCon, Immatics, InFlarX, Innovent, Labcorp, Replimune, and Haystack; his institution also received research funding from Bristol-Myers Squibb, Roche-Genentech, Array, and Merck Sharp & Dhome, all of which took place outside the submitted work. N.K. received personal fees, travel costs, and speaker’s honoraria from Astellas, Novartis, Ipsen, and Photocure, all of which took place outside the submitted work. M.P.L. has received project-specific research funding from Roche, Novartis, Molecular Partners, and Oncobit., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Although ACE2 is the primary receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, a systematic assessment of host factors that regulate binding to SARS-CoV-2 spike protein has not been described. Here, we use whole-genome CRISPR activation to identify host factors controlling cellular interactions with SARS-CoV-2. Our top hit was a TLR-related cell surface receptor called leucine-rich repeat-containing protein 15 (LRRC15). LRRC15 expression was sufficient to promote SARS-CoV-2 spike binding where they form a cell surface complex. LRRC15 mRNA is expressed in human collagen-producing lung myofibroblasts and LRRC15 protein is induced in severe Coronavirus Disease 2019 (COVID-19) infection where it can be found lining the airways. Mechanistically, LRRC15 does not itself support SARS-CoV-2 infection, but fibroblasts expressing LRRC15 can suppress both pseudotyped and authentic SARS-CoV-2 infection in trans. Moreover, LRRC15 expression in fibroblasts suppresses collagen production and promotes expression of IFIT, OAS, and MX-family antiviral factors. Overall, LRRC15 is a novel SARS-CoV-2 spike-binding receptor that can help control viral load and regulate antiviral and antifibrotic transcriptional programs in the context of COVID-19 infection., Competing Interests: The authors declare no competing interests., (Copyright: © 2023 Loo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: High tumor mutational burden (TMB) is associated with a favorable outcome in metastatic melanoma patients treated with immune checkpoint inhibitors. However, data are limited in the adjuvant setting. As BRAF mutated patients have an alternative with targeted adjuvant therapy, it is important to identify predictive factors for relapse and recurrence-free survival (RFS) in patients receiving adjuvant anti-PD-1 antibodies., Methods: We evaluated 165 melanoma patients who started adjuvant anti-PD-1 antibody therapy at our center between March 2018 and September 2019. The initial tumor stage was assessed at the beginning of therapy according to the 8th edition of the AJCC Cancer Staging Manual. Tumor and normal tissue of the high-risk stages IIIC/D/IV were sequenced using a 700 gene NGS panel., Results: The tumor stages at the beginning of adjuvant anti-PD-1 therapy were as follows: N = 80 stage IIIA/B (48%), N = 85 stage IIIC/D/IV (52%). 72/165 patients (44%) suffered a relapse, 44/72 (61%) with only loco regional and 28/72 (39%) with distant metastases. Sequencing results were available from 83 to 85 patients with stage IIIC/D/IV. BRAF mutation status (HR 2.12, 95% CI 1.12-4.08; p = 0.022) and TMB (HR 7.11, 95% CI 2.19-23.11; p = 0.001) were significant and independent predictive factors for relapse-free survival (RFS)., Conclusion: BRAF mutation status and TMB were independent predictive factors for RFS. Patients with BRAF V600E/K mutation and TMB high had the best outcome. A classification based on BRAF mutation status and TMB is proposed to predict RFS in melanoma patients with adjuvant anti-PD-1 therapy., (© 2022. The Author(s).)

Rationale: Coronavirus disease 2019 (COVID-19) can lead to acute respiratory distress syndrome with fatal outcomes. Evidence suggests that dysregulated immune responses, including autoimmunity, are key pathogenic factors. Objectives: To assess whether IgA autoantibodies target lung-specific proteins and contribute to disease severity. Methods: We collected 147 blood, 9 lung tissue, and 36 BAL fluid samples from three tertiary hospitals in Switzerland and one in Germany. Severe COVID-19 was defined by the need to administer oxygen. We investigated the presence of IgA autoantibodies and their effects on pulmonary surfactant in COVID-19 using the following methods: immunofluorescence on tissue samples, immunoprecipitations followed by mass spectrometry on BAL fluid samples, enzyme-linked immunosorbent assays on blood samples, and surface tension measurements with medical surfactant. Measurements and Main Results: IgA autoantibodies targeting pulmonary surfactant proteins B and C were elevated in patients with severe COVID-19 but not in patients with influenza or bacterial pneumonia. Notably, pulmonary surfactant failed to reduce surface tension after incubation with either plasma or purified IgA from patients with severe COVID-19. Conclusions: Our data suggest that patients with severe COVID-19 harbor IgA autoantibodies against pulmonary surfactant proteins B and C and that these autoantibodies block the function of lung surfactant, potentially contributing to alveolar collapse and poor oxygenation.

Purpose: The first randomized trial of adjuvant treatment with checkpoint inhibitor in stage II melanoma reported a significant reduction in risk of tumor recurrence. This study evaluates two independent data sets to further document survival probabilities for patients with primary stage I and II melanoma., Patients and Methods: The Central Malignant Melanoma Registry (CMMR) in Germany evaluated 17,544 patients with a primary diagnosis of stage I and II melanoma from 2000 to 2015. The exploratory cohort consisted of 6,725 patients from the Center for Dermato-Oncology at the University of Tübingen, and the confirmatory cohort consisted of 10,819 patients from 11 other German centers. Survival outcomes were compared with published American Joint Committee on Cancer version 8 (AJCCv8) stage I and II survival data., Results: For the two CMMR cohorts in stage IA compared with the AJCCv8 cohort, melanoma-specific survival rates at 10 years were 95.1%-95.6% versus 98%; 89.7%-90.9% versus 94% in stage IB; 80.7%-83.1% versus 88% in stage IIA; 72.0%-79.9% versus 82% in stage IIB; and 57.6%-64.7% versus 75% in stage IIC, respectively. Recurrence rates were approximately twice as high as melanoma-specific mortality rates in stages IA-IIA., Conclusion: The melanoma-specific survival rates in the two CMMR cohorts across stages I and II are less favorable than published in AJCCv8. This has important implications for the consideration of adjuvant treatment in this population.

Cancer treatment with immune checkpoint blockade (ICB) often induces immune-related adverse events (irAEs). We hypothesized that proteins coexpressed in tumors and normal cells could be antigenic targets in irAEs and herein described DITAS (discovery of tumor-associated self-antigens) for their identification. DITAS computed transcriptional similarity between lung tumors and healthy lung tissue based on single-sample gene set enrichment analysis. This identified 10 lung tissue-specific genes highly expressed in the lung tumors. Computational analysis was combined with functional T cell assays and single-cell RNA sequencing of the antigen-specific T cells to validate the lung tumor self-antigens. In patients with non-small cell lung cancer (NSCLC) treated with ICB, napsin A was a self-antigen that elicited strong CD8 + T cell responses, with ICB responders harboring higher frequencies of these CD8 + T cells compared with nonresponders. Human leukocyte antigen (HLA) class I ligands derived from napsin A were present in human lung tumors and in nontumor lung tissues, and napsin A tetramers confirmed the presence of napsin A-specific CD8 + T cells in blood and tumors of patients with NSCLC. Napsin A-specific T cell clonotypes were enriched in lung tumors and ICB-induced inflammatory lung lesions and could kill immortalized HLA-matched NSCLC cells ex vivo. Single-cell RNA sequencing revealed that these T cell clonotypes expressed proinflammatory cytokines and cytotoxic markers. Thus, DITAS successfully identified self-antigens, including napsin A, that likely mediate effective antitumor T cell responses in NSCLC and may simultaneously underpin lung irAEs.

Coronavirus disease 2019 (COVID-19) is the most notable pandemic of the modern era. A relationship between ascorbate (vitamin C) and COVID-19 severity is well known, whereas the role of other vitamins is less understood. The present study compared the blood levels of four vitamins in a cohort of COVID-19 patients with different severities and uninfected individuals. Serum concentrations of ascorbate, calcidiol, retinol, and α-tocopherol were measured in a cohort of 74 COVID-19 patients and 8 uninfected volunteers. The blood levels were statistically compared and additional co-morbidity factors were considered. COVID-19 patients had significantly lower plasma ascorbate levels than the controls (p-value < 0.001), and further stratification revealed that the controls had higher levels than fatal, critical, and severe COVID-19 cases (p-values < 0.001). However, no such trend was observed for calcidiol, retinol, or α-tocopherol (p-value ≥ 0.093). Survival analysis showed that plasma ascorbate below 11.4 µM was associated with a lengthy hospitalization and a high risk of death. The results indicated that COVID-19 cases had depleted blood ascorbate associated with poor medical conditions, confirming the role of this vitamin in the outcome of COVID-19 infection.

Melanoma incidence rates are high among individuals with fair skin and multiple naevi. Established prognostic factors are tumour specific, and less is known about prognostic host factors. A total of 556 stage I to stage IV melanoma patients from Germany with phenotypic and disease-specific data were analysed; 64 of these patients died of melanoma after a median follow-up time of 8 years. Germline DNA was assessed by the HumanCoreExome BeadChip and data of 356,384 common polymorphisms distributed over all 23 chromosomes were used for a genome-wide analysis. A suggestive genome-wide significant association of the intronic allele rs7551288*A with diminished melanoma-specific survival was detected ( p = 2 × 10 -6 ). The frequency of rs7551288*A was 0.43 and was not associated with melanoma risk, hair and eye colour, tanning and total naevus count. Cox regression multivariate analyses revealed a 5.31-fold increased risk of melanoma-specific death for patients with the rs7551288 A/A genotype, independent of tumour thickness, ulceration and stage of disease at diagnoses. The variant rs7551288 belongs to the DHCR24 gene, which encodes Seladin-1, an enzyme involved in the biosynthesis of cholesterol. Further investigations are needed to confirm this genetic variant as a novel prognostic biomarker and to explore whether specific treatment strategies for melanoma patients might be derived from it.

Purpose: Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms., Experimental Design: Response to vismodegib was evaluated in a cohort of 148 laBCC patients. Comprehensive genomic and transcriptomic profiling was performed in a subset of five intrinsically resistant BCC (IR-BCC)., Results: We identified that IR-BCC represents 6.1% of laBCC in the studied cohort. Prior treatment with chemotherapy was associated with IR. Genetic events that were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyperactivation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on the BCC cell line further confirmed that YAP1 overexpression increases the cell proliferation rate., Conclusions: IR to vismodegib is a rare event in laBCC. IR-BCCs frequently harbor resistance mutations in the Hh pathway, but also are characterized by hyperactivation of the HIPPO-YAP and WNT pathways., (©2022 The Authors; Published by the American Association for Cancer Research.)