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Distinct Immune-microenvironment Construction Diversely Responded to Induction Immunotherapy among Multiple Primary Lung Adenocarcinoma

ABSTRACT: We performed an integrated multi-omics analysis including single-cell RNA sequencing in one multiple lung nodules patient treated with pembrolizumab. We found that responded nodule showed notably higher infiltrating macrophages and lymphocytes through mIHC. Much higher genomic somatic copy number variants events were observed in two non-responded nodules. scRNA highlighted HLA-related gene down-regulation in both non-responded nodules indicating one of its immune evasion mechanisms. Moreover, significantly high proportion of Tissue resident memory T cells were found in responded nodule which has been validated to be both predictive and prognostic signature among multiple cancer types through external datasets. As for macrophages, MDSC-like subtype was predominantly observed in responded nodule while TAM-like subtype mainly in other two non-responded nodules. Through TCGA-LUAD cohort, MDSC-like macrophages showed inferior prognostic value compared to TAM-like macrophages suggesting a potential resistant mechanism along with increased responded immune infiltration. This study provides an in-depth multi-omics analysis on firstly reported multiple primary lung adenocarcinoma receiving immunotherapy and describes potential early immune signals responding to immunotherapy, as well as impaired antigen-presenting process in sub-solid nodules which may attribute to primary resistant of immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146100 | GEO | 2021/04/28

REPOSITORIES: GEO

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Project description:Root-microbe interaction and its specialized root nodule structures and functions are well studied. In contrast, leaf nodules harboring microbial endophytes in special glandular leaf structures have only recently gained increased interest as plant-microbe phyllosphere interactions. Here, we applied a comprehensive metabolomics platform in combination with natural product isolation and characterization to dissect leaf and leaf nodule metabolism and functions in Ardisia crenata (Primulaceae) and Psychotria punctata (Rubiaceae). The results indicate that abiotic stress resilience plays an important part within the leaf nodule symbiosis of both species. Both species showed metabolic signatures of enhanced nitrogen assimilation/dissimilation pattern and increased polyamine levels in nodules compared to leaf lamina tissue potentially involved in senescence processes and photosynthesis. Multiple links to cytokinin and REDOX-active pathways were found. Our results further demonstrate that secondary metabolite production by endophytes is a key feature of this symbiotic system. Multiple anhydromuropeptides (AhMP) and their derivatives were identified as highly characteristic biomarkers for nodulation within both species. A novel epicatechin derivative was structurally elucidated with NMR and shown to be enriched within the leaf nodules of A. crenata. This enrichment within nodulated tissues was also observed for catechin and other flavonoids indicating that flavonoid metabolism may play an important role for leaf nodule symbiosis of A. crenata. In contrast, pavettamine was only detected in P. punctata and showed no nodule specific enrichment but a developmental effect. Further natural products were detected, including three putative unknown depsipeptide structures in A. crenata leaf nodules. The analysis presents a first metabolomics reference data set for the intimate interaction of microbes and plants in leaf nodules, reveals novel metabolic processes of plant-microbe interaction as well as the potential of natural product discovery in these systems.

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Distinct Immune-microenvironment Construction Diversely Responded to Induction Immunotherapy among Multiple Primary Lung Adenocarcinoma

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