Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell Analyses

Abstract

Summary To guide the design of immunotherapy strategies for patients with early stage lung tumors, we developed a multiscale immune profiling strategy to map the immune landscape of early lung adenocarcinoma lesions to search for tumor-driven immune changes. Utilizing a barcoding method that allows a simultaneous single cell analysis of the tumor, non-involved lung and blood cells together with multiplex tissue imaging to assess spatial cell distribution, we provide a detailed immune cell atlas of early lung tumors. We show that stage I lung adenocarcinoma lesions already harbor significantly altered T cell and NK cell compartments. Moreover, we identified changes in tumor infiltrating myeloid cell (TIM) subsets that likely compromise anti-tumor T cell immunity. Paired single cell analyses thus offer valuable knowledge of tumor-driven immune changes, providing a powerful tool for the rational design of immune therapies.

Low PD-1 Expression in Cytotoxic CD8+ Tumor-Infiltrating Lymphocytes Confers an Immune-Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value

“…These cells are likely responsible for IFNg secretion, the most powerful PD-L1 stimulating factor (45). Secondly, KRAS mutation was associated with a reduced expression of PD-L1, as previously documented (44), while, at variance with the literature (26,46), EGFR mutation did not statistically impact on this parameter. It has been extensively reported that tumors with a greater mutational load could generate more neoantigens leading to a larger repertoire of tumor-specific T cells (41).…”

Understanding the tumor immune microenvironment (TIME) for effective therapy

“…We believe that further stratification of patients on the basis of not only their tumor type but also their TIME type will yield better insight into overall survival and the likelihood of response to immunotherapeutics, and will provide vast datasets to help identify new druggable targets. This progress will be garnered by using the most cutting-edge techniques in multiparametric imaging 106 , mass cytometry 107,108 and single-cell RNA sequencing 109 . Critical to this goal is that improved resolution of cellular composition and analysis of functional status and spatial distribution must be paired with relevant patient outcomes (Fig.…”

Recent advances in understanding the complexities of metastasis

“…Advances in sequencing platforms 38– 40 have shown us that micro-evolutionary genetic changes, including somatic mutations, copy number alterations and structural variants in the genome, alongside heritable factors, are detectable independently at both primary and secondary sites as a result of site-specific, context-dependent selective pressures 6, 33, 41– 43 . This has allowed the identification of hallmark mutational signatures in many different cancer types as well as their metastases 44– 47 and is facilitating a deeper subclassification of specific cancers 48– 52 .…”