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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.

Single-cell RNA sequencing data and TCR data from "Autoreactive napsin A-specific T cells are enriched in lung tumors and inflammatory lung lesions during checkpoint blockade", Berner et al. &nbsp

The recent emergence of multiple SARS-CoV-2 variants has caused considerable concern due to reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is therefore paramount to develop therapeutic strategies that inhibit all known and future SARS-CoV-2 variants. Here we report that all SARS-CoV-2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma, and Delta, exhibit enhanced binding affinity to clinical grade and phase 2 tested recombinant human soluble ACE2 (APN01). Importantly, soluble ACE2 neutralized infection of VeroE6 cells and human lung epithelial cells by multiple VOC strains with markedly enhanced potency when compared to reference SARS-CoV-2 isolates. Effective inhibition of infections with SARS-CoV-2 variants was validated and confirmed in two independent laboratories. These data show that SARS-CoV-2 variants that have emerged around the world, including current VOC and several variants of interest, can be inhibited by soluble ACE2, providing proof of principle of a pan-SARS-CoV-2 therapeutic.

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 bronchoalveolar lavage 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 bronchoalveolar lavage 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 against pulmonary surfactant proteins B and C and that these antibodies block the function of lung surfactant, potentially contributing to alveolar collapse and poor oxygenation. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background Long-term survival of stage IV melanoma patients has improved significantly with the development of immune checkpoint inhibitors (CIs). Reliable biomarkers to predict response and clinical outcome are needed. Methods We investigated the role of melanoma-associated antibodies as predictive markers for CI therapy in two independent cohorts. In cohort 1, a prospective study, we measured specific antibodies before treatment, after one week and after six to nine weeks of treatment. Cohort 2 consisted of serum samples prior to CI therapy initiation. ELISA assays were performed to quantify specific IgG directed against melanocyte differentiation antigens tyrosinase-related proteins 1 and 2 (TRP1/TYRP1 and TRP2/TYRP2), glycoprotein 100 (gp100), MelanA/MART1, and the cancer-testis antigen NY-ESO-1. Response was defined as either complete or partial remission on CT scan according to RECIST 1.1. Results In cohort 1, baseline levels of these antibodies were higher in the responder group, although statistical significance was only reached for NY-ESO-1 (p = 0.007). In cohort 2, significantly higher antibody baseline levels for MelanA/MART1 (p = 0.003) and gp100 (p = 0.029) were found. After pooling the results from both cohorts, higher levels of MelanA/MART1 (p = 0.013), TRP1/TYRP1 (p = 0.048), TRP2/TYRP2 (p = 0.047) and NY-ESO-1 (p = 0.005) specific antibodies at baseline were independently associated with response. Conclusions Melanoma-associated antibodies may be candidate biomarkers for response and survival in metastatic melanoma patients being treated with CIs. These markers may be used to complement patient assessment, in combination with PD-L1 status, tumor-infiltrating lymphocytes and tumor mutational burden, with the aim to predict outcome of CI treatment in patients with metastatic melanoma. Trial registration Ethikkommission Ostschweiz, EKOS 16/079 https://ongoingprojects.swissethics.ch/runningProjects_list.php?q=%28BASECID~contains~2016-00998%29&orderby=dBASECID. Electronic supplementary material The online version of this article (10.1186/s40425-019-0523-2) contains supplementary material, which is available to authorized users.

Stefan Diem,1–3,* Mirjam Fässler,2,* Omar Hasan Ali,2,4 Marco Siano,1 Rebekka Niederer,2 Fiamma Berner,2 Guillaume-Alexandre Roux,2 Christoph Jakob Ackermann,1 Sabine Schmid,1 Sabine Güsewell,5 Martin Früh,1,6 Lukas Flatz1,2,4,5,7 1Department of Oncology/Haematology, Kantonsspital St. Gallen, St. Gallen, Switzerland; 2Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland; 3Department of Oncology/Haematology, Spital Grabs, St. Gallen, Switzerland; 4Department of Dermatology, University Hospital Zürich, Zürich, Switzerland; 5Clinical Trials Unit, Kantonsspital St. Gallen, St. Gallen, Switzerland; 6University of Bern, Bern, Switzerland; 7Department of Dermatology/Allergology, Kantonsspital St. Gallen, St. Gallen, Switzerland *These authors contributed equally to this work Background: Prognosis of metastatic non-small cell lung cancer significantly improved with the availability of checkpoint inhibitors (anti-PD-1/PD-L1). Unfortunately, reliable biomarkers to predict treatment benefit are lacking.Patients and methods: We prospectively collected clinical and laboratory data of 56 non-small cell lung cancer patients treated with a checkpoint inhibitor. The aim was to identify baseline parameters correlating with worse outcome and to create a risk score that enabled to stratify patients into different risk groups. As inflammation is known to promote tumor growth, we focused on inflammation markers in the blood. Disease control (DC) was defined ascomplete response, partial response, and stable disease on CT scan according to RECIST 1.1.Results: Half of the patients achieved DC. Four parameters differed significantly between the DC group and the no disease control group: Eastern Cooperative Oncology Group performance status (P=0.009), number of organs with metastases (P=0.001), lactate dehydrogenase (P=0.029), and ferritin (P=0.005). A risk score defined as the number of these parameters (0= no risk factor) exceeding a threshold (Eastern Cooperative Oncology Group performance status ≥2, number of organs with metastases ≥4, lactate dehydrogenase ≥262U/L, and ferritin ≥241 µg/L) was associated with overall survival and progression-free survival. Overall survival at 6 and 12 months is as follows: Scores 0–1: 95% and 95%; Score 2: 67% and ≤33%; Scores 3–4: 15% and 0%. Progression-free survival at 6 and 12 months is as follows: Scores 0–1: 81% and 50%; Score 2: 25% and ≤25%; Scores 3–4: 0% and 0%.Conclusion: We propose an easy-to-apply risk score categorizing patients into different risk groups before treatment start with a PD-1/PD-L1 antibody. Keywords: NSCLC, checkpoint inhibitor, biomarkers, risk score, response, survival

Purpose: Immune checkpoint inhibitor (ICI)-induced hepatitis belongs to the frequently occurring immune-related adverse events (irAEs), particularly with the combination therapy involving ipilimumab and nivolumab. However, predisposing factors predicting the occurrence of ICI-induced hepatitis are barely known. We investigated the association of preexisting autoantibodies in the development of ICI-induced hepatitis in a prospective cohort of cancer patients. Methods: Data from a prospective biomarker cohort comprising melanoma and non-small cell lung cancer (NSCLC) patients were used to analyze the incidence of ICI-induced hepatitis, putatively associated factors, and outcome. Results: 40 patients with melanoma and 91 patients with NSCLC received ICI between July 2016 and May 2019. 11 patients developed ICI-induced hepatitis (8.4%). Prior to treatment, 45.5% of patients in the hepatitis cohort and 43.8% of the control cohort showed elevated titers of autoantibodies commonly associated with autoimmune liver diseases (p = 0.82). We found two nominally significant associations between the occurrence of ICI-induced hepatitis and HLA alleles associated with autoimmune liver diseases among NSCLC patients. Of note, significantly more patients with ICI-induced hepatitis developed additional irAEs in other organs (p = 0.0001). Neither overall nor progression-free survival was affected in the hepatitis group. Conclusion: We found nominally significant associations of ICI-induced hepatitis with two HLA alleles. ICI-induced hepatitis showed no correlation with liver-specific autoantibodies, but frequently co-occurred with irAEs affecting other organs. Unlike other irAEs, ICI-induced hepatitis is not associated with a better prognosis.