Single-Cell Characterization of Pulmonary Nodules Implicates Suppression of Immunosurveillance across Early Stages of Lung Adenocarcinoma

Authors

Jane Yanagawa
Linh M Tran
Ramin Salehi-Rad
Raymond J Lim
Camelia Dumitras
Eileen Fung
William D Wallace
Ashley E Prosper
Gregory Fishbein
Conor Shea
Rui Hong
Bitta Kahangi
John J Deng
Adam C Gower
Bin Liu
Joshua D Campbell
Sarah A Mazzilli
Jennifer E Beane
Humam Kadara
Marc E Lenburg
Avrum E Spira
Denise R Aberle
Kostyantyn Krysan
Steven M Dubinett

Publication Date

10-2-2023

Journal

Cancer Research

Abstract

UNLABELLED: A greater understanding of molecular, cellular, and immunological changes during the early stages of lung adenocarcinoma development could improve diagnostic and therapeutic approaches in patients with pulmonary nodules at risk for lung cancer. To elucidate the immunopathogenesis of early lung tumorigenesis, we evaluated surgically resected pulmonary nodules representing the spectrum of early lung adenocarcinoma as well as associated normal lung tissues using single-cell RNA sequencing and validated the results by flow cytometry and multiplex immunofluorescence (MIF). Single-cell transcriptomics revealed a significant decrease in gene expression associated with cytolytic activities of tumor-infiltrating natural killer and natural killer T cells. This was accompanied by a reduction in effector T cells and an increase of CD4+ regulatory T cells (Treg) in subsolid nodules. An independent set of resected pulmonary nodules consisting of both adenocarcinomas and associated premalignant lesions corroborated the early increment of Tregs in premalignant lesions compared with the associated normal lung tissues by MIF. Gene expression analysis indicated that cancer-associated alveolar type 2 cells and fibroblasts may contribute to the deregulation of the extracellular matrix, potentially affecting immune infiltration in subsolid nodules through ligand-receptor interactions. These findings suggest that there is a suppression of immune surveillance across the spectrum of early-stage lung adenocarcinoma.

SIGNIFICANCE: Analysis of a spectrum of subsolid pulmonary nodules by single-cell RNA sequencing provides insights into the immune regulation and cell-cell interactions in the tumor microenvironment during early lung tumor development.

Keywords

Humans, Monitoring, Immunologic, Tomography, X-Ray Computed, Adenocarcinoma of Lung, Lung Neoplasms, Multiple Pulmonary Nodules, Adenocarcinoma, Tumor Microenvironment

Comments

Supplementary Materials

Data Availability Statement

PMID: 37477508