Wagenlehner, F. | Search bioRxiv

bioRxiv2023

T cells in testicular germ cell tumors: new evidence of fundamental contributions by rare subsets

BACKGROUNDImmune cell infiltration is heterogeneous but common in testicular germ cell tumors (TGCT) and pre-invasive germ cell neoplasia in situ (GCNIS). Tumor-infiltrating T cells including regulatory T (Treg) and follicular helper T (Tfh) cells are found in other cancer entities, but their contributions to TGCT are unknown. METHODSHuman testis specimens from independent patient cohorts were analyzed using immunohistochemistry, flow cytometry and single-cell RNA sequencing (scRNA-seq) with special emphasis on delineating T cell subtypes. RESULTSProfound changes in immune cell composition within TGCT, shifting from macrophages in normal testes to T cells plus B and dendritic cells in TGCT, were documented. In most samples (96%), the CD4+ T cell frequency exceeded that of CD8+ cells, with decreasing numbers from central to peripheral tumor areas, and to tumor-free, contralateral testes. T cells including Treg and Tfh were most abundant in seminoma compared to mixed tumors and embryonal carcinoma. CONCLUSIONDespite considerable heterogeneity between patients, T cell subtypes form a key part of the TGCT microenvironment. The novel finding of rare Treg and Tfh cells in human testis suggests their involvement in TGCT pathobiology, with implications for understanding tumor progression, to assess patients prognosis, and as putative targets for personalized immunotherapy.

cancer biology↗

bioRxiv2023

Proteomic adaptations in the kidney reveal orchestration of local and secreted antimicrobial peptides in human pyelonephritis

Pyelonephritis (PN) is a frequent bacterial infection of the kidney and is often associated with severe diseases, organ loss and sepsis. Antibiotics are the cornerstone of therapy, however, increasing antibiotic resistance threatens therapy success and necessitates novel treatment strategies. Various proteins, such as antimicrobial peptides (AMPs), are key molecules of the innate immune response and insights into their regulation may help overcome multi-drug resistance and severe diseases. Using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS), several cellular, biological, and metabolic processes important for the antimicrobial response were identified, including a significant increase in previously undescribed proteins in human PN with antimicrobial function. Among others, we observed elevation of AMPs, such as calprotectin, azurocidin-1, and cathepsin G in the kidney, which we validated in the urine. Additionally, we observed a negative correlation of azurocidin-1 with plasma levels of C-reactive protein suggesting that the presence in the kidney may protect from severe diseases and systemic inflammation. This study represents the first renal proteomic dataset of human PN, enabling novel insights into the expression of AMPs in the context of PN. Lay SummaryGrowing antimicrobial resistance necessitates a better understanding of the expression of proteins that are critical for the immune response. Using mass spectrometry we identified AMPs in the kidney and urine of PN patients. Elevated levels of the AMP azurocidin-1 was associated with reduced systemic inflammation, indicated by lower C-reactive protein. Overall, this study identified expression of previously undescribed AMPs in the context of human PN. These proteins may play a pivotal role in protection from severe diseases and systemic inflammation.

immunology↗