Differences of molecular events driving pathological and radiological progression of lung adenocarcinoma.

BACKGROUND: Ground-glass opacity (GGO)-like lung adenocarcinoma (LUAD) has been detected increasingly in the clinic and its inert property and superior survival indicate unique biological characteristics. However, we do not know much about them, which hampers identification of key reasons for the inert property of GGO-like LUAD. METHODS: Using whole-exome sequencing and RNA sequencing, taking into account both radiological and pathological classifications of the same 197 patients concomitantly, we systematically interrogate genes driving the progression from GGO to solid nodule and potential reasons for the inertia of GGO. Using flow cytometry and IHC, we validated the abundance of immune cells and activity of cell proliferation. FINDINGS: Identifying the differences between GGO and solid nodule, we found adenocarcinoma in situ/minimally invasive adenocarcinoma (AIS/MIA) and GGO-like LUAD exhibited lower TP53 mutation frequency and less active cell proliferation-related pathways than solid nodule in LUAD. Identifying the differences in GGO between AIS/MIA and LUAD, we noticed that EGFR mutation frequency and CNV load were significantly higher in LUAD than in AIS/MIA. Regulatory T cell was also higher in LUAD, while CD8+ T cell decreased from AIS/MIA to LUAD. Finally, we constructed a transcriptomic signature to quantify the development from GGO to solid nodule, which was an independent predictor of patients' prognosis in 11 external LUAD datasets. INTERPRETATION: Our results provide deeper insights into the indolent nature of GGO and provide a molecular basis for the treatment of GGO-like LUAD. FUNDING: This study was supported in part by the National Natural Science Foundation of China (32170657), the National Natural Science Foundation of China (82203037), and Shanghai Sailing Program (22YF1408900).

Elevated Mast Cell Abundance Is Associated with Enrichment of CCR2+ Cytotoxic T Cells and Favorable Prognosis in Lung Adenocarcinoma.

Mast cells constitute indispensable immunoregulatory sentinel cells in the tumor microenvironment. A better understanding of the regulation and functions of mast cells in lung adenocarcinoma (LUAD) could uncover therapeutic approaches to reprogram the immunosuppressive tumor microenvironment. Here, we performed flow cytometry and single-cell RNA sequencing (scRNA-seq) of patient LUAD samples to comprehensively characterize LUAD-infiltrating mast cells. Mast cells exhibited functional heterogeneity and were enriched in LUAD with ground-glass opacity features (gLUAD). The mast cells in gLUAD exhibited proinflammatory and chemotactic properties while those in radiologically solid LUAD (sLUAD) were associated with tumor angiogenesis. Mast cells were an important source of CCL2 and correlated with the recruitment of CCR2+ CTL, a specific subcluster of preexhausted T cells with tissue-resident memory phenotype and enhanced cytotoxicity. Increased infiltration of mast cells and CCR2+ CTLs and their colocalization showed a strong association with favorable prognosis after surgery but were not associated with improved survival after chemotherapy. Collectively, these findings reveal a key role of mast cells in LUAD and their potential cross-talk with CTLs, suggesting that targeting mast cells may be an immunotherapeutic strategy for LUAD. SIGNIFICANCE: Comprehensive characterization of mast cells in lung adenocarcinoma elucidates their heterogeneity and identifies interplay between mast cells and CCR2+ T cells that is associated with a favorable prognosis.

Subsolid Lung Adenocarcinomas: Radiological, Clinical and Pathological Features and Outcomes.

Lung adenocarcinomas manifesting as subsolid nodules usually have a favorable prognosis. This study aimed to have a comprehensive investigation of the radiological and clinicopathologic features and oncological outcomes of subsolid nodules. Between March 2010 and December 2015, 865 patients with surgically resected clinical IA subsolid lung adenocarcinoma were retrospectively reviewed. Patients were classified into the pure ground-glass nodules (GGN) (pGGN [n = 358], without solid component on lung and mediastinal windows), heterogeneous GGN (hGGN [n = 65], only with solid components on lung window), and real part-solid nodule (rPSN [n = 442], with solid component on both lung and mediastinal windows) groups. The clinicopathological features and survival time of the three groups were compared between groups. There was a significant increase in median tumor size (P < 0.001), solid component size measured at lung window (LW-SCS) (P < 0.001), and the proportion of invasive adenocarcinoma subtypes (P < 0.001) from pGGNs to hGGNs to rPSNs. After adjustment for LW-SCS, adenocarcinomas with predominant lepidic patterns were still more common in hGGNs than in rPSNs (P = 0.009). Patients with rPSNs had a significantly worse recurrence-free survival (RFS) than those with pGGNs and hGGNs (5-year: 91.9% versus 100% versus 100%, P < 0.001). Multivariate Cox analyses revealed that gender (both P < 0.05) and clinical T category (based on lung window [LW-cT] [P = 0.002] or mediastinal window [MW-cT] [P < 0.001]) were independent prognostic factors of RFS in the rPSN group. HGGNs represented as an intermediate subtype between pGGNs and rPSNs. Both pGGNs and hGGNs had excellent outcomes, while rPSNs exhibited a worse prognosis than them. Clinical T category and gender had prognostic implications for rPSNs.

Subsolid Lesions Exceeding 3 Centimeters: The Ground-Glass Opacity Component Still Matters.

BACKGROUND: Recent studies on the favorable prognosis of ground-glass opacities (GGO) featured lung adenocarcinoma compared with solid nodules were limited to small tumors measuring 3.0 cm or less. This study investigated whether the GGO component could predict better prognosis in patients with large subsolid lesions exceeding 3 cm compared with small solid nodules within the same clinical T category. METHODS: From 2010 to 2015, 1010 patients with completely resected clinical N0 lung adenocarcinoma were enrolled, including 860 solid lesions and 150 subsolid lesions exceeding 3 cm. To analyze the prognostic significance of the GGO component, propensity score matching adjusting the solid component size was performed. RESULTS: After propensity score matching, 144 pairs of patients were analyzed. The mean size of the solid component was 23.7 mm in the GGO group and 24.4 mm in the solid group (P = .450). The GGO group had significantly better overall survival (P = .011) and recurrence-free survival (P = .003), which were also validated in patients with solid-predominant lesions. Subgroup analysis showed the GGO group was associated with better prognosis in each clinical T category. CONCLUSIONS: The prognosis of patients with GGO lesions exceeding 3 cm was better than that of patients with small solid lesions, even within the same clinical T category. Clinical T classification incorporating the GGO component may provide better prognostic prediction for patients with lung cancer exceeding 3 cm.