Single-cell evaluation reveals innate immune arrested and lymphocytes shifting that promote development of preinvasive lung adenocarcinoma

Cancer immunotherapy has demonstrated promising efficacy in the neoadjuvant setting for treating early-stage non-small cell lung cancer (NSCLC). However, immunotherapy for preinvasive or early invasive disease has been largely overlooked. We performed single-cell RNA and TCR sequencing for 266,804 high quality cells as well as whole exome sequencing (WES) and multiplex immunofluorescence (mIF) on 31 pathologically confirmed preinvasive or early invasive lung adenocarcinoma (LUAD) with paired adjacent tissues. We identified CD47-SIRPA as a key mediator of arresting innate immune response in the tumor microenvironment of preinvasive LUAD. Additionally, highly intercellular heterogeneity was observed and overexpression of KRT18 and PHLDA2 may promote malignant progression during carcinogenesis. By integrating network analysis among tumor and immune cells, we established comprehensive interactive landscape of preinvasive and early invasive LUAD, determining an imbalance of Th17/Treg and increased LAMP3+DCs may boost early tumor development. Our study provides comprehensive genomic and immune features of preinvasive LUAD, highlighting novel therapeutic targets which shed light on understanding how tumor microenvironment shapes neoplastic progression during early evolution of LUAD.