Genetic and immunologic features of recurrent stage I lung adenocarcinoma

Johannes R Kratz,Alexis J Combes,Vincent Chan,Michael J Mann,Jessica Tsui,Jen C Lee,Arjun A Rao,Jack Z Li,David M Jablons,Vivianne W Ding,Matthew F Krummel

doi:10.1038/s41598-021-02946-0

Abstract

Although surgery for early-stage lung cancer offers the best chance of cure, recurrence still occurs between 30 and 50% of the time. Why patients frequently recur after complete resection of early-stage lung cancer remains unclear. Using a large cohort of stage I lung adenocarcinoma patients, distinct genetic, genomic, epigenetic, and immunologic profiles of recurrent tumors were analyzed using a novel recurrence classifier. To characterize the tumor immune microenvironment of recurrent stage I tumors, unique tumor-infiltrating immune population markers were identified using single cell RNA-seq on a separate cohort of patients undergoing stage I lung adenocarcinoma resection and applied to a large study cohort using digital cytometry. Recurrent stage I lung adenocarcinomas demonstrated higher mutation and lower methylation burden than non-recurrent tumors, as well as widespread activation of known cancer and cell cycle pathways. Simultaneously, recurrent tumors displayed downregulation of immune response pathways including antigen presentation and Th1/Th2 activation. Recurrent tumors were depleted in adaptive immune populations, and depletion of adaptive immune populations and low cytolytic activity were prognostic of stage I recurrence. Genomic instability and impaired adaptive immune responses are key features of stage I lung adenocarcinoma immunosurveillance escape and recurrence after surgery.

Highlights

Surgery for early-stage lung cancer offers the best chance of cure, recurrence still occurs between 30 and 50% of the time
In order to incorporate time-to-recurrence data, a score that predicts the risk of recurrence for each patient in the The Cancer Genome Atlas (TCGA) lung adenocarcinoma was developed
Elastic net penalization using cross-validation yielded a parsimonious set of genes associated with recurrence in 500 patients with stage I-IV lung adenocarcinoma in the TCGA cohort (Supplementary Table S1)

Summary

Introduction

Surgery for early-stage lung cancer offers the best chance of cure, recurrence still occurs between 30 and 50% of the time. While multiple studies have described the genetic, genomic, and epigenetic alterations in tumor vs normal tissue[14,15], only a handful of groups have investigated the biology of early-stage lung cancer recurrence[16,17]. These studies have primarily focused on mutation profiles associated with recurrence by utilizing targeted NGS panels of known cancer mutations[16,17]. More comprehensive and specific descriptions of the tumor immune microenvironment characteristic of early recurrence after surgery are still needed to guide our current immunotherapy treatments and reveal novel immunotherapy targets

Methods

Results

Conclusion