Biomarkers for predicting response to anti-programmed death-1 (PD-1) immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) remain in demand. Since anti-tumor immune activation is a ...process, early dynamic changes of the acute-phase reactant C reactive protein (CRP) may serve as a predictive on-treatment biomarker. In a retrospective (N=105) and prospective (N=108) ICB-treated NSCLC cohort, early CRP kinetics were stratified after the start of immunotherapy until weeks 4, 6, and 12 as follows: an early doubling of baseline CRP followed by a drop below baseline (CRP flare-responder), a drop of at least 30% below baseline without prior flare (CRP responders), or those who remained as CRP non-responders. In our study, we observed characteristic longitudinal changes of serum CRP concentration after the initiation of ICB. In the prospective cohort, N=40 patients were defined as CRP non-responders, N=39 as CRP responders, and N=29 as CRP flare-responders with a median progression-free survival (PFS) of 2.4, 8.1, and 14.3 months, respectively, and overall survival (OS) of 6.6, 18.6, and 32.9 months (both log-rank p<0.001). Of note, CRP flare-responses, characterized by a sharp on-treatment CRP increase in the first weeks after therapy initiation, followed by a decrease of CRP serum level below baseline, predict ICB response as early as 4 weeks after therapy initiation. Of note, early CRP kinetics showed no predictive value for chemoimmunotherapy or when steroids were administered concurrently. On-treatment CRP kinetics had a predictive value for both major histological NSCLC subtypes, adenocarcinoma and squamous cell carcinoma. The results were verified in an independent retrospective cohort of 105 patients. In conclusion, CRP flare predicted anti-PD-1 monotherapy response and survival in two independent cohorts including a total of 213 patients with NSCLC, regardless of histology. Due to its wide clinical availability, early CRP kinetics could become an easily determined, cost-efficient, and non-invasive biomarker to predict response to checkpoint inhibitors in NSCLC within the first month.
Background Chest wall abnormalities are a poorly studied complication after treatment for childhood cancer. Chest wall abnormalities are not well-described in the literature, and little is known on ...the impact on daily life of survivors. Methods We investigated prevalence and risk factors of chest wall abnormalities in childhood cancer survivors in a nationwide, population-based cohort study (Swiss Childhood Cancer Survivor Study) with a questionnaire survey. We then interviewed a nested sample of survivors to validate types of chest wall abnormalities and understand their impact on the daily life of survivors. Results Forty-eight of 2382 (95%CI 2-3%) survivors reported a chest wall abnormality. Risk factors were older age at cancer diagnosis (16-20 years; OR 2.5, 95%CI 1.0-6.1), lymphoma (OR 3.8, 95%CI 1.2-11.4), and central nervous system tumors (OR 9.5, 95%CI 3.0-30.1) as underlying disease, and treatment with thoracic radiotherapy (OR 2.0, 95%CI 1.0-4.2), surgery to the chest (OR 4.5, 95%CI 1.8-11.5), or chemotherapy (OR 2.9, 95%CI 1.0-8.1). The nature of the chest wall abnormalities varied and included thoracic wall deformities (30%), deformations of the spine (5%) or both (55%), and scars (10%). Chest wall abnormalities affected daily life in two thirds (13/20) of those who reported these problems and necessitated medical attention for 15 (75%) survivors. Conclusion It is important that, during follow-up care, physicians pay attention to chest wall abnormalities, which are rare late effects of cancer treatment, but can considerably affect the well-being of cancer survivors. Keywords: Chest wall deformity, Swiss Childhood Cancer Survivor Study, Late effects, Cancer treatment
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
To assess whether IgA autoantibodies target lung-specific proteins and contribute to disease severity.
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.
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.
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.
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.
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.
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.
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.
Type II pneumocytes represent the main target cells of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory viruses. The killing of infected type II pneumocytes leads to the release of not only viral antigens, but also of self-antigens, such as type II pneumocyte-associated antigens (type II PAAs). These self-antigens can lead to the priming and activation of CD8+ T cells. Patients with non-severe Coronavirus disease-19 (COVID-19) have an efficient and targeted viral clearance of SARS-CoV-2, suggesting a previous infection with other respiratory viruses, such as influenza. In the case of a subsequent infection with a virus like SARS-CoV-2, the swift T cell response by pre-existing autoreactive T cells could have a protective effect in these pre-immunized patients by promoting the killing of infected type II pneumocytes. This suggests that autoreactive type II PAA-specific and COVID-19-specific T cells may synergistically protect from severe COVID-19 infection, although this theory will require further studies for validation. On the other hand, patients that do not harbor such protective autoreactive T cells have an impaired viral clearance and develop severe COVID-19. Display omitted
•Type II PAA-specific T cells are present in the blood of COVID-19 patients.•Patients with non-severe COVID-19 harbor increased numbers of type II PAA-specific T cells.•The protective effect of type II PAA-specific T cells is independent of patient age.•A T cell-mediated autoimmune response against type II PAAs may be protective in COVID-19.
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.
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.
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.
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.
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.
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•Systemic immune signatures shortly after the start of ICI therapy are linked to irAEs•ICI-treated patients with cancer with irAEs show an expansion of Ki-67+ T cell subsets•IFN-γ and IFN-γ-related proteins CXCL9/10/11 are increased in ICI-treated patients with irAEs•Early blood ICI immune signatures may provide a predictive biomarker profile for irAEs
ICIs have significantly improved the treatment of a wide range of cancers. However, ICIs can cause life-threatening autoimmune side effects. There are currently no biomarkers to predict which patients are more likely to develop such side effects. Researchers at the University of Zurich, the Kantonsspital St. Gallen, and the University of Tübingen have identified early changes occurring in the blood of patients with cancer treated with ICIs. These changes predict the development of autoimmune toxicity. These findings will allow us to determine which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring. Thus, the findings here may help improve care for patients with cancer by providing timely and life-saving management strategies for patients at high risk.
Immune checkpoint inhibitors have revolutionized cancer treatment; however, they are associated with potentially life-threatening immune-related toxicities. In a prospective multi-center study of patients with melanoma and NSCLC, Nuñez et al. identified immune signatures occurring early after the start of treatment potentially predicting the onset of adverse events.
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