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Introduction: Ground glass opacity featured lung adenocarcinomas (GGO-LUAD) display more indolent biological behavior than solid nodule featured lung adenocarcinomas (SN-LUAD) and have an excellent prognosis. However, the cellular immune characteristics of GGO-LUAD remain poorly understood. Methods: Immunohistochemistry technique was performed to stain related immune markers (CD8, CD103, CD20, CD138, CD4, FOXP3, CD68, CD163, PD-1 and PD-L1) and TGF-β from 15 patients with pure GGO-LUAD and 15 patients with SN-LUAD tissue sections (Paired cohort), and then, the related markers with significant differences were verified on 10 patients (Verified cohort) with both pure GGO-LUAD and SN-LUAD. For localization analysis of CD68 + tumor-associated macrophages (TAMs) and FOXP3 + Terg cells in tumor areas, pure GGO-LUAD and SN-LUAD were also stained for simultaneous detection of pan-CK, CD68 and FOXP3 by multiplex immunofluorescence. Results: In the Paired cohort, compared with SN-LUAD, only the infiltration of TAMs and Treg cells was significantly lower in GGO-LUAD. The infiltration of the remaining immune cells including CD8 + T cells, CD4 + T cells, CD103 + T cells, CD20 + B cells and CD138 + Plasma cells in GGO-LUAD, although relatively low, was not significantly different. Meanwhile, the expression of TGF-β was significantly higher in SN-LUAD. And the above results have also been confirmed in the Verified cohort. Moreover, there was no significantly difference in PD-L1 expression in GGO-LUAD compared to SN-LUAD both in the Paired cohort and Verified cohort. Conclusions: GGO-LUAD demonstrates an overall less active immune landscape as compared with SN-LUAD. TAMs and TGF-β may play an important role in the progression of GGO-LUAD. More importantly, PD-L1 expression in GGO-LUAD is comparable to that in SN-LUAD, indicating that there may be other reasons for the insensitivity of GGO-LUAD to immunotherapy. [ABSTRACT FROM AUTHOR]

• Membrane PD-L1 expression was rarely observed in the presence of ALK rearrangements. • Tumor bed infiltration CD8 + T cell more frequent in tumors with ALK mutations. • CD8+ T cells infiltrating ALK+ tumors were unable to express IFNG. Several lines of evidence have demonstrated that programmed cell death 1 (PD-1) inhibitors as monotherapies for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer have little clinical activity. The underlying mechanisms remain not understood. In this study, using immunohistochemistry and in situ RT-PCR assays, we examined the expression of programmed cell death ligand 1 (PD-L1), PD-1, CD8, and interferon gamma (IFN-γ) in tumors. Both epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-positive tumors were associated with low or absent membrane PD-L1 expression. Interestingly, unlike EGFR-mutant tumors with few tumor-infiltrating CD8+ T cells, a significant number of PD-1-positive CD8+ T cells infiltrated the ALK-positive tumor bed; however, these cells did not express IFNG mRNA. These results demonstrate that the ALK-positive tumor microenvironment suppresses the immune function of tumor-infiltrating CD8+ T cells through a PD-1/PD-L1-independent mechanism, which might lead to the inability of ALK-positive tumors to respond to PD-1/PD-L1-based immunotherapy. [ABSTRACT FROM AUTHOR]