Global evolution of the tumor microenvironment associated with progression from preinvasive invasive to invasive human lung adenocarcinoma

• Published in: Cell reports (Cambridge) Vol. 39; no. 1; p. 110639
• Main Authors: Altorki, Nasser K., Borczuk, Alain C., Harrison, Sebron, Groner, Lauren K., Bhinder, Bhavneet, Mittal, Vivek, Elemento, Olivier, McGraw, Timothy E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.04.2022; Elsevier
• Subjects: Adenocarcinoma - pathology; Adenocarcinoma of Lung - genetics; CP: Cancer; CT scan density; extracellular matrix; GGO; Humans; lung ground glass lesions; Lung Neoplasms - pathology; Neoplasm Invasiveness - pathology; preinvasive lung adenocarcinoma; Retrospective Studies; Tregs; Tumor Microenvironment; lung ground glass lesions; Tregs; CP: Cancer; tumor microenvironment; CT scan density; GGO; extracellular matrix; preinvasive lung adenocarcinoma
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110639

To investigate changes in the tumor microenvironment (TME) during lung cancer progression, we interrogate tumors from two chest computed tomography (CT)-defined groups. Pure non-solid (pNS) CT density nodules contain preinvasive/minimally invasive cancers, and solid density nodules contain invasive cancers. Profiling data reveal a dynamic interaction between the tumor and its TME throughout progression. Alterations in genes regulating the extracellular matrix and genes regulating fibroblasts are central at the preinvasive state. T cell-mediated immune suppression is initiated in preinvasive nodules and sustained with rising intensity through progression to invasive tumors. Reduced T cell infiltration of the cancer cell nests is more frequently associated with preinvasive cancers, possibly until tumor evolution leads to a durable, viable invasive phenotype accompanied by more varied and robust immune suppression. Upregulation of immune checkpoints occurs only in the invasive nodules. Throughout progression, an effector immune response is present but is effectively thwarted by the immune-suppressive elements. [Display omitted] •Non-solid CT density lung adenocarcinomas are predominantly pre/minimally invasive•Immune-suppressive Tregs are increased in non-solid nodules•ECM genes are increased in non-solid nodules, implicating fibroblasts activation•Increased immune suppression parallels progression to invasion CT-scan-identified lung nodules present a significant clinical challenge. Altorki et al. define characteristics, both immune-context and microenvironment features, distinguishing normal lung, preinvasive, and invasive nodules. By capturing early features of disease progression, they inform future interception strategies and identify key questions to be investigated in mechanistic studies.