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Simple Summary: Immune checkpoint inhibitors (ICI) have the potential to induce serious and unpredictable immune-related adverse events (irAEs), the underlying mechanisms of which remain incompletely understood. In this study, we investigated the relationship between irAEs and the expression of IFN-inducible chemokines and cytokines in patients with solid tumours treated with PD-(L)1 inhibitors. We analysed plasma levels of various IFN-related cytokines at different time points in patients categorized by irAE development and severity. We found that patients with serious irAEs showed significant increases in CXCL9, CXCL10, CXCL11, IL-18 and IL-10 at the onset of the irAE compared to patients with mild irAEs and those without irAEs. Additionally, IL-18 emerged as a promising predictive biomarker for serious irAE development. In summary, this study provides valuable insights into the immune responses associated with irAEs and proposes potential predictive markers for their severity. Immune checkpoint inhibitors (ICI) have the potential to trigger unpredictable immune-related adverse events (irAEs), which can be severe. The underlying mechanisms of these events are not fully understood. As PD-L1 is upregulated by IFN, the heightened immune activation resulting from PD-1/PD-L1 inhibition may enhance the IFN response, triggering the expression of IFN-inducible genes and contributing to irAE development and its severity. In this study, we investigated the interplay between irAEs and the expression of IFN-inducible chemokines and cytokines in 134 consecutive patients with solid tumours treated with PD-(L)1 inhibitors as monotherapy or in combination with chemotherapy or other immunotherapy agents. We compared the plasma levels of IFN-associated cytokines (CXCL9/10/11, IL-18, IL-10, IL-6 and TGFβ) at various time points (at baseline, at the onset of irAE and previous to irAE onset) in three patient groups categorized by irAE development and severity: patients with serious irAEs, mild irAEs and without irAEs after PD-(L)1 inhibitors. No differences were observed between groups at baseline. However, patients with serious irAEs exhibited significant increases in CXCL9/10/11, IL-18 and IL-10 levels at the onset of the irAE compared to baseline. A network analysis and correlation patterns highlighted a robust relationship among these chemokines and cytokines at serious-irAE onset. Combining all of the analysed proteins in a cluster analysis, we identified a subgroup of patients with a higher incidence of serious irAEs affecting different organs or systems. Finally, an ROC analysis and a decision tree model proposed IL-18 levels ≥ 807 pg/mL and TGFβ levels ≤ 114 pg/mL as predictors for serious irAEs in 90% of cases. In conclusion, our study elucidates the dynamic changes in cytokine profiles associated with serious irAE development during treatment with PD-(L)1 inhibitors. The study's findings offer valuable insights into the intricate IFN-induced immune responses associated with irAEs and propose potential predictive markers for their severity. [ABSTRACT FROM AUTHOR]

Simple Summary: This study provides novel information about the role of neutrophils in malignant pleural effusion (MPE) and hallmarks their clinical relevance. Since these cells have emerged as important regulators of cancer, we characterized their phenotype and functions in MPE microenvironment. We found that neutrophil-derived products (degranulation molecules and neutrophil extracellular traps (NETs)) were increased in MPE. In addition, NETs were associated with a worse outcome in lung adenocarcinoma patients with MPE. Malignant pleural effusion (MPE) is a common severe complication of advanced lung adenocarcinoma (LAC). Neutrophils, an essential component of tumor infiltrates, contribute to tumor progression and their counts in MPE have been associated with worse outcome in LAC. This study aimed to evaluate phenotypical and functional changes of neutrophils induced by MPE to determine the influence of MPE immunomodulatory factors in neutrophil response and to find a possible association between neutrophil functions and clinical outcomes. Pleural fluid samples were collected from 47 LAC and 25 heart failure (HF) patients. We measured neutrophil degranulation products by ELISA, oxidative burst capacity and apoptosis by flow cytometry, and NETosis by fluorescence. The concentration of degranulation products was higher in MPE-LAC than in PE-HF. Functionally, neutrophils cultured with MPE-LAC had enhanced survival and neutrophil extracellular trap (NET) formation but had reduced oxidative burst capacity. In MPE, NETosis was positively associated with MMP-9, P-selectin, and sPD-L1 and clinically related to a worse outcome. This is the first study associating NETs with a worse outcome in MPE. Neutrophils likely contribute to tumor progression through the release of NETs, suggesting that they are a potential therapeutic target in LAC. [ABSTRACT FROM AUTHOR]

Simple Summary: This study contributes to the characterization of CD8+ HLA-DR+ T cell mediated-mechanisms involved in the anti-tumor response in breast cancer patients who respond to neoadyuvant chemotherapy (NACT). Cultures with plasma from responder (R), but not from non-responder (NR), patients increased the intracellular production of cytotoxic molecules and pro-inflammatory cytokines in CD8+HLA-DR+ T cells. However, the addition of neutralizing anti-IFN-γ or anti-IL-12 antibodies to cultures with plasma from R patients decreased this effector function on CD8+HLA-DR+ T cells. These results suggest the presence of soluble factors in the plasma of R patients inducing the effector function of CD8+HLA-DR+ T cells. Cytotoxic T lymphocyte (CTLs) activation is an independent predictor of response to neoadjuvant chemotherapy (NACT) in breast cancer (BC) patients. Here, we go deeper into the function of CD8+ HLA-DR+ T cells from NACT treated HER2 negative BC patients. Flow cytometry analysis revealed that CD8+ HLA-DR+ T cell percentage was increased in NACT responder (R) compared to non-responder (NR) patients. R patients with ER-/PR- hormone receptors had the highest CD8+ HLA-DR+ T cell frequencies, while no differences were found when patients were classified according to cancer stage or menopause status. Interestingly, the cytotoxicity and production of anti-tumor cytokines were enhanced when CD8+ HLA-DR+ T cells from healthy donors were cultured with plasma from R, but not from NR patients. The induced anti-tumor profile of CD8+ HLA-DR+ T cells was associated with plasmatic IL-12 and IFN-γ levels, increased cytokines in R patients. IL-12 or IFN-γ neutralization decreased cytotoxic activity and TNF-α production by cultured CD8+ HLA-DR+ T cells in R plasma presence. All these data suggest that an effective response to NACT in BC patients is associated with increased IL-12 or IFN-γ levels involved in the induction of cytotoxic and pro-inflammatory mechanisms in CD8+ HLA-DR+ T cells. [ABSTRACT FROM AUTHOR]