Center for Medical Ethics and Health Policy Staff Publications
Publication Date
7-18-2022
Journal
Cancer Research
DOI
10.1158/0008-5472.CAN-21-3506
PMID
35709756
PMCID
PMC9296613
PubMedCentral® Posted Date
1-18-2023
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Adenocarcinoma, Adenocarcinoma of Lung, Humans, Lung Neoplasms, Macrophages, Tumor Microenvironment, lung adenocarcinoma, adenocarcinoma in situ, invasive adenocarcinoma, trabectedin, tumor immune microenvironment, mass cytometry, tumor-associated macrophage, PD-1, immune checkpoint inhibitor, systems immunology
Abstract
Although the majority of patients with advanced lung adenocarcinoma (LUAD) are eligible to receive immune checkpoint blockade, approximately 80% of these tumors are resistant to this therapeutic approach. Insights at the single-cell level into mechanisms that drive LUAD tumorigenesis and the relationship of LUAD histologic heterogeneity to response to immune checkpoint blockade could help identify biomarkers and potential combinational approaches to improve immunotherapy efficacy. Here we used a genetically engineered mouse model that replicates the development of human LUAD through a spectrum of pre-invasive to invasive adenocarcinoma histologic subtypes. A systems onco-immunology approach of integrating the analytical power and unique, complementary capabilities of time-of-flight mass cytometry (CyTOF) and imaging mass cytometry was leveraged to identify cellular and spatial immune contextures in LUAD. Comprehensive investigation of mouse and human LUAD using these single-cell proteomics platforms showed that LUAD progression is associated with spatiotemporal evolution of tumor-associated macrophages in the tumor-immune microenvironment, which governs tumor response to immunotherapy. PD-1 was expressed in a highly plastic tumor-promoting subtype of tumor-associated macrophages that develops during tumor progression from pre-invasive to invasive adenocarcinoma, controls the lymphocyte-depleted niche of invasive tumors, and protects tumor cells in the solid histologic components of the tumor. Longitudinal, multi-dimensional single-cell analyses of LUAD tumorigenesis revealed dynamic alteration of immunoregulatory PD-1-expressing tumor-associated macrophages that can be targeted to overcome resistance to checkpoint immunotherapy.
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