Acquisition of Discrete Immune Suppressive Barriers Contributes to the Initiation and Progression of Preinvasive to Invasive Human Lung Cancer

Overview

Journal bioRxiv

Date 2025 Jan 13

PMID 39803458

Authors

Liron Yoffe

Bhavneet Bhinder

Sung Wook Kang

Haoran Zhang

Arshdeep Singh

Hiranmayi Ravichandran

Geoffrey Markowitz

Mitchell Martin

Junbum Kim

Chen Zhang

Olivier Elemento

Wesley Tansey

Stewart Bates

Timothy E McGraw

Alain Borczuk

Hyun-Sung Lee

Nasser K Altorki

Vivek Mittal

Affiliations

Soon will be listed here.

Abstract

Computerized chest tomography (CT)-guided screening in populations at risk for lung cancer has increased the detection of preinvasive subsolid nodules, which progress to solid invasive adenocarcinoma. Despite the clinical significance, there is a lack of effective therapies for intercepting the progression of preinvasive to invasive adenocarcinoma. To uncover determinants of early disease emergence and progression, we used integrated single-cell approaches, including scRNA-seq, multiplexed imaging mass cytometry and spatial transcriptomics, to construct the first high-resolution map of the composition, lineage/functional states, developmental trajectories and multicellular crosstalk networks from microdissected non-solid (preinvasive) and solid compartments (invasive) of individual part-solid nodules. We found that early disease initiation and subsequent progression are associated with the evolution of immune-suppressive cellular phenotypes characterized by decreased cytotoxic CD8 T and NK cells, increased T cell exhaustion and accumulation of immunosuppressive regulatory T cells (Tregs) and M2-like macrophages expressing TREM2. Within Tregs, we identified a unique population of 4-1BB+ Treg subset enriched for the IL2-STAT5 suppressive pathway with transcription profiles supporting discrete metabolic alterations. Spatial analysis showed increased density of suppressive immune cells around tumor cells, increased exhaustion phenotype of both CD4 and CD8 T cells expressing chemokine CXCL13, and spatial microcomplex of endothelial and lymphocyte interactions within tertiary lymphoid structures. The single-cell architecture identifies determinants of early disease emergence and progression, which may be developed not only as diagnostic/prognostic biomarkers but also as targets for disease interception. Additionally, our dataset constitutes a valuable resource for the preinvasive lung cancer research community.

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