Decreased IL-6 and NK Cells in Early-Stage Lung Adenocarcinoma Presenting as Ground-Glass Opacity

Abstract

BackgroundLung ground-glass opacities (GGOs) are an early manifestation of lung adenocarcinoma. It is of great value to study the changes in the immune microenvironment of GGO to elucidate the occurrence and evolution of early lung adenocarcinoma. Although the changes of IL-6 and NK cells in lung adenocarcinoma have caught global attention, we have little appreciation for how IL-6 and NK cells in the lung GGO affect the progression of early lung adenocarcinoma.MethodsWe analyzed the RNA sequencing data of surgical specimens from 21 patients with GGO-featured primary lung adenocarcinoma and verified the changes in the expression of IL-6 and other important immune molecules in the TCGA and GEO databases. Next, we used flow cytometry to detect the protein expression levels of important Th1/Th2 cytokines in GGO and normal lung tissues and the changes in the composition ratio of tumor infiltrating lymphocytes (TILs). Then, we analyzed the effect of IL-6 on NK cells through organoid culture and immunofluorescence. Finally, we explored the changes of related molecules and pathway might be involved.ResultsIL-6 may play an important role in the tumor microenvironment of early lung adenocarcinoma. Further research confirmed that the decrease of IL-6 in GGO tissue is consistent with the changes in NK cells, and there seems to be a correlation between these two phenomena.ConclusionThe IL-6 expression status and NK cell levels of early lung adenocarcinoma as GGO are significantly reduced, and the stimulation of IL-6 can up-regulate or activate NK cells in GGO, providing new insights into the diagnosis and pathogenesis of early lung cancer.

The immune microenvironment of lung adenocarcinoma featured with ground‐glass nodules

“…Another study also found a trend of decreasing numbers and functions of NK cells in nLung, GGNs and SNs 25 . Zhang et al found that this change in NK cells was synchronized with IL‐6 by scRNA‐seq of nLung and GGNs, and further in vitro induced culture revealed that IL‐6 did have a promotional effect on the proliferation of NK cells, and this effect was particularly evident in GGNs 38 . The role of combined cytokine supplementation therapies based on NK cells in NSCLC has recently been demonstrated, and approaches such as NK‐92 and chimeric antigen receptor (CAR)‐transduced NK cells are being explored in lung cancer 39 .…”

“…CTL and NK cells are the mainstay of tumor cell killing in the adaptive and intrinsic immune systems, respectively, by the classical mechanism of the perforin‐granzyme (or granule exocytosis) pathway (Figure 1). 51 However, according to the above summary, the number and function of CD8+ T cells and NK cells are reduced in GGNs compared with nLung, 38,43 which is attributed to the fact that their function receives influence from other immune components and tumor cells. Tumor cells upregulate heterogeneous ligands such as HLA‐C molecules, and other reasons include shedding of NKG2D ligands, and release of immunosuppressive cytokines (i.e., IL‐6, IL‐10, and TGF‐β) 39 …”

“… 25 Zhang et al found that this change in NK cells was synchronized with IL‐6 by scRNA‐seq of nLung and GGNs, and further in vitro induced culture revealed that IL‐6 did have a promotional effect on the proliferation of NK cells, and this effect was particularly evident in GGNs. 38 The role of combined cytokine supplementation therapies based on NK cells in NSCLC has recently been demonstrated, and approaches such as NK‐92 and chimeric antigen receptor (CAR)‐transduced NK cells are being explored in lung cancer. 39 Therefore, fully utilizing the antitumor function of NK cells in GGNs and preventing tumor cell‐induced decline in NK cell function may be the direction of treatment of GGNs.…”

Multiplexed Analysis of Endogenous Guanidino Compounds via Isotope-Coded Doubly Charged Labeling: Application to Lung Cancer Tissues as a Case

“…Lung cancer is divided into various types and subtypes . Among them, adenocarcinoma, the main subtype of non-small-cell lung cancer, accounts for 50% of all lung cancer cases. , Ground-glass cells are often a precursor to lung cancer, usually adenocarcinoma of the lung . Realizing simultaneous quantification of endogenous metabolites in multiple types of lung cancer tissues can not only improve the analytical efficiency and intuitively show the distribution differences in the target analytes but also minimize the deviation in the analytical result and provide reliable information for relevant clinical research.…”