Antti Ellonen

Oxidative stress response (OSR) is suggested as a therapeutic target in triple negative breast cancer (TNBC). However, the cell type specificity and spatial distribution of OSR genes and proteins remain poorly defined. We re-analyzed public datasets, demostrating high OSR gene expression in TNBC tumor cells. We generated a multiplex immunofluorescence dataset of 345 TNBC samples that showed OSR proteins GCLC and NQO1 are differentially expressed across tumor, immune, and stromal cells, and elevated in inflamed regions. We identified a mesenchymal-like tumor cell state characterized by co-expression of GCLC and vimentin (GCLC⁺VIM⁺), with increased proliferation and reduced anastasis-associated signatures, suggesting a vulnerability to chemotherapy. Consistently, TNBC cell lines with higher GCLC expression showed increased sensitivity to cisplatin. Moreover, patients with higher proportions of GCLC⁺VIM⁺ tumor cells had longer overall survival. Our findings indicate that OSR proteins are expressed in spatially and phenotypically distinct tumor microenvironments, and that the GCLC⁺VIM⁺ tumor cell state is associated with favorable outcomes in TNBC.

Background and purpose: Tobacco smoking was prognostic in B-cell lymphomas in the pre-rituximab era, but the association with modern treatment, stage, subtypes, and survival outcomes remains unclear. Patient/material and methods: All patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) from Turku and Tampere University Hospitals 2009–2019 were identified. Population-based data from electronic medical records included demographics, tumour histology, Ann Arbor staging, and treatments. Smoking status was extracted with a deep learning-based natural language processing algorithm. Kaplan–Meier overall survival (OS) estimates and adjusted hazard ratios (HRs) were calculated. Results: With a median follow-up of 96 months, 1,258 patients with DLBCL and 529 with FL were included. In DLBCL, the 5-year OS rate was 61%, 53%, and 45% among never, former, and persistent smokers, respectively. Persistent smoking remained an independent prognostic factor for shorter OS, HR 1.27 (95% confidence interval 1.10–1.60) after adjustment for comorbidities and completed treatment. The prognosis of FL was indolent with no difference in OS regardless of smoking status, with 5-year OS rates of 79%, 75%, and 74% among never, former, and persistent smokers, respectively. Smokers were younger at diagnosis, while other baseline demographics were similar. No differences in the systemic therapy use were observed between the different smoking categories in both FL and DLBCL. Interpretation: Overall and lymphoma-specific mortality is increased in persistent smokers with DLBCL compared with never smokers. Smoking prevention and cessation support remains of utmost importance.

Inhibiting oxidative stress response (OSR) proteins has been suggested as a therapeutic strategy in triple negative breast cancer (TNBC). However, the cell type specificity and spatial distribution of OSR genes and proteins, such as GCLC and NQO1, is unknown. Using single cell and spatial transcriptomics datasets we found that OSR genes were highly expressed in TNBC tumor cells, which localized in spatial clusters. Multiplex immunofluorescence imaging of 345 TNBC samples from 186 patients demonstrated that OSR proteins GCLC and NQO1 exhibit distinct expression profiles across tumor, immune, and stromal cell populations and are elevated in inflamed histological regions. Tumor cell OSR protein expression was associated with the composition of the adjacent cellular neighborhood. Furthermore, we identified GCLC and vimentin positive (GCLC+VIM+) mesenchymal-like tumor cells, residing near immune cells and exhibiting increased proliferation and decreased anastasis signatures, suggesting sensitivity to chemotherapy. Across a panel of thirteen TNBC cell lines, GCLC expression was positively correlated with sensitivity to cisplatin. Cox regression analysis revealed that patients with higher proportions of GCLC+VIM+ tumor cells had a longer overall survival. Collectively, our results demonstrate that individual OSR proteins are expressed in distinct microenvironments and tumor cell states, potentially contributing to patient outcomes.