Respiratory viral infections prime accelerated lung cancer growth [scRNA-Seq]
The COVID-19 pandemic has highlighted long-term health consequences of viral pneumonia, yet its impact on cancer development and progression remains poorly understood. Here, we show that prior SARS-CoV-2 or influenza infection accelerates lung tumor progression by reprogramming the local immune landscape. To define mechanisms underlying infection-induced tumor promotion, we performed single-cell RNA-seq on whole-lung cells from KP mice at 6 weeks (PBS_T6, IAV_T6) and 12 weeks (PBS_T12, IAV_T12) after tumor induction, along with tumor-free PBS and IAV controls (time matched to T6). Across conditions, scRNA-seq revealed that prior viral pneumonia programs a pro-tumor lung microenvironment marked by increased pro-tumor myeloid programs and diminished anti-tumor CD8+ T cell immunity. Notably, we identified a dominant SiglecF^hi tumor-associated neutrophil subset enriched in infected tumors that exhibits hypoxia/glycolysis- and immunosuppression-associated transcriptional programs and shows the strongest predicted interactions with progenitor and tumor epithelial populations. Overall design: KP mice infected with IAV for 3 weeks were i.t. administered Ad5-SPC-Cre virus to initiate lung tumorigenesis. Lung single-cell suspensions were generated at weeks 6 (early-stage) and 12 (late-stage) after tumor induction for scRNA-Seq analysis. Tumor free PBS- and IAV-treated mice served as controls. Each group was representing pooled samples from 3-5 mice. Single-cell libraries were prepared using the Chromium Single Cell 3' Reagent Kit (10x Genomics) following the manufacturer's protocol.