Oral lichen planus (OLP) is a common chronic inflammatory disorder of the oral mucosa with an unclear etiology. Several types of immune cells are involved in the pathogenesis of OLP.
We used ...single-cell RNA sequencing and immune repertoire sequencing to characterize the mucosal immune microenvironment of OLP. The presence of tissue-resident memory CD8+ T cells are validated by multiplex immunofluorescence.
We generated a transcriptome atlas from four OLP biopsy samples and their paired peripheral blood mononuclear cells (PBMCs), and compared them with two healthy tissues and three healthy PBMCs samples. Our analysis revealed activated tissue-resident memory CD8+ T cells in OLP tissues. T cell receptor repertoires displayed apperant clonal expansion and preferrential gene pairing in OLP patients. Additionally, obvious BCR clonal expansion was observed in OLP lesions. Plasmacytoid dendritic cells, a subtype that can promote dendritic cell maturation and enhance lymphocyte cytotoxicity, were identified in OLP. Conventional dendritic cells and macrophages are also found to exhibit pro-inflammatory activity in OLP. Cell-cell communication analysis reveals that fibroblasts might promote the recruitment and extravasation of immune cells into connective tissue.
Our study provides insights into the immune ecosystem of OLP, serving as a valuable resource for precision diagnosis and therapy of OLP.
Prior data have variably implicated the inactivation of the mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) complex with increased tumor sensitivity to immune checkpoint inhibitors (ICI). Herein, ...we examined the association between mSWI/SNF variants and clinical outcomes to ICIs. We correlated somatic loss-of-function (LOF) variants in a predefined set of mSWI/SNF genes (
, and
) with clinical outcomes in patients with cancer treated with systemic ICIs. We identified 676 patients from Dana-Farber Cancer Institute (DFCI, Boston, MA) and 848 patients from a publicly available database from Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY) who met the inclusion criteria. Multivariable analyses were conducted and adjusted for available baseline factors and tumor mutational burden. Median follow-up was 19.6 (17.6-22.0) months and 28.0 (25.0-29.0) months for the DFCI and MSKCC cohorts, respectively. Seven solid tumor subtypes were examined. In the DFCI cohort, LOF variants of mSWI/SNF did not predict improved overall survival (OS), time-to-treatment failure (TTF), or disease control rate. Only patients with renal cell carcinoma with mSWI/SNF LOF showed significantly improved OS and TTF with adjusted HRs (95% confidence interval) of 0.33 (0.16-0.7) and 0.49 (0.27-0.88), respectively, and this was mostly driven by
In the MSKCC cohort, where only OS was captured, LOF mSWI/SNF did not correlate with improved outcomes across any tumor subtype. We did not find a consistent association between mSWI/SNF LOF variants and improved clinical outcomes to ICIs, suggesting that mSWI/SNF variants should not be considered as biomarkers of response to ICIs.
Direct immunofluorescence and immune function and patients with oral lichen planusThe etiology of oral lichen planus (OLP) is unknown, our purpose was to evaluate the diagnostic value of direct ...immunofluorescence (DIF) and to investigate the immune functions in OLP.
We enrolled 65 patients with suspected lesions of OLP and 47 controls. In all participants, clinical and serologic testing were conducted. The histopathologic and DIF tests were conducted in 65 patients. The severity of OLP was evaluated by reticular/hyperkeratotic, erosive/erythematous, ulcerative (REU) scoring system.
By hematoxylin and eosin (H&E) staining and DIF examination, 71.2% (42/59) were diagnosed as OLP, 28.8% (17/59) were diagnosed as non-OLP. DIF demonstrated 64.3% positive reactivity with 2 distinct distribution patterns and 8 staining patterns. Compared to the controls, serum IgA in OLP was higher (P < 0.01), and serum CD3+ cells, IgM, IgE, C3 and C4 were lower (P < 0.05). Pearson correlation analysis in OLP revealed correlations between REU score and IgM, IgA of DIF (r = 0.54, P = 0.026; and r = 0.56, P = 0.020, respectively), between serum IgG and IgG of DIF (r = 0.51, P = 0.038), between serum CD4+ and the ratio of CD4+/CD8+, IgM in DIF (r = −0.50, P = 0.048; and r = −0.54, P = 0.031, respectively), between serum CD8+ and IgM, IgA in DIF (r = 0.52, P = 0.038; and r = −0.50, P = 0.047, respectively).
A combination of H&E test and DIF is useful for the diagnosis of OLP. Compared to controls, immune changes happen to patients with OLP. There are significant associations between the OLP lesions and general cellular and humoral immune status, localized humoral immune response.
Oral squamous cell carcinoma (OSCC) stands as a predominant and perilous malignant neoplasm globally, with the majority of cases originating from oral potential malignant disorders (OPMDs). Despite ...this, effective strategies to impede the progression of OPMDs to OSCC remain elusive. In this study, we established mouse models of oral carcinogenesis via 4‐nitroquinoline 1‐oxide induction, mirroring the sequential transformation from normal oral mucosa to OPMDs, culminating in OSCC development. By intervening during the OPMDs stage, we observed that combining PD1 blockade with photodynamic therapy (PDT) significantly mitigated oral carcinogenesis progression. Single‐cell transcriptomic sequencing unveiled microenvironmental dysregulation occurring predominantly from OPMDs to OSCC stages, fostering a tumor‐promoting milieu characterized by increased Treg proportion, heightened S100A8 expression, and decreased Fib_Igfbp5 (a specific fibroblast subtype) proportion, among others. Notably, intervening with PD1 blockade and PDT during the OPMDs stage hindered the formation of the tumor‐promoting microenvironment, resulting in decreased Treg proportion, reduced S100A8 expression, and increased Fib_Igfbp5 proportion. Moreover, combination therapy elicited a more robust treatment‐associated immune response compared with monotherapy. In essence, our findings present a novel strategy for curtailing the progression of oral carcinogenesis.
In oral carcinogenesis, various cell types, including epithelial cells (Epi_Cxcl9) and macrophages (Macro_S100a8), exhibit significant expression of inflammatory‐related cytokines such as S100A8/S100A9. The overexpressed inflammatory cytokines recruit numerous immunosuppressive cell subsets (Tregs, Macro_Cd274, CD8_Tex, etc.). PD1 monoclonal antibody (PD1 mAb) can specifically block the functional inhibition of CD8_Tex by Macro_Cd274, but simultaneously accompanied by an increase in Treg proportion. Photodynamic therapy (PDT) not only directly kills abnormal cells but also reduces the proportion of Treg. Compared with monotherapy, the combination of PD1 mAb and PDT can reshape the microenvironment and induce a stronger therapy‐related inflammatory response, thereby preventing oral carcinogenesis.
To assess the efficacy of photodynamic therapy (PDT) for oral squamous cell carcinoma (OSCC), literature on this topic from Embase, PubMed, and Web of Science were obtained and analyzed. The response ...and recurrence rates with 95% confidence intervals (CI) were calculated using the DerSimonia–Laird method. The pooled complete response (CR) rate from the included studies was 0.799 (95% CI: 0.708–0.867), while the overall response (OR) rate was 0.967 (95% CI: 0.902–0.989). The recurrence rate (RR) was 0.158 (95% CI: 0.090–0.264). A subgroup analysis of lesion site, photosensitizer, laser type, radiant exposure, and power density revealed no statistically significant differences. In general, PDT is effective for the treatment of early OSCC. Investigations on the influence of PDT on the survival of OSCC patients, optimization of the treatment regimen, and evaluation of response after treatment are still needed.
Knowledge of the changes in the immune microenvironment during pulmonary bacterial acute and chronic infections is limited. The dissection of immune system may provide a basis for effective ...therapeutic strategies against bacterial infection. Here, we describe a single immune cell atlas of mouse lungs after acute and chronic Pseudomonas aeruginosa infection using single‐cell transcriptomics, multiplex immunohistochemistry, and flow cytometry. Our single‐cell transcriptomic analysis revealed large‐scale comprehensive changes in immune cell composition and high variation in cell–cell interactions after acute and chronic P. aeruginosa infection. Bacterial infection reprograms the genetic architecture of immune cell populations. We identified specific immune cell types, including Cxcl2+ B cells and interstitial macrophages, in response to acute and chronic infection, such as their proportions, distribution, and functional status. Importantly, the patterns of immune cell response are drastically different between acute and chronic infection models. The distinct molecular signatures highlight the importance of the highly dynamic cell–cell interaction process in different pathological conditions, which has not been completely revealed previously. These findings provide a comprehensive and unbiased immune cellular landscape for respiratory pathogenesis in mice, enabling further understanding of immunologic mechanisms in infection and inflammatory diseases.
Mouse lung cell subtypes with the most significant gene expression changes in acute and chronic pulmonary infection. In the acute infection condition, activated receptors and their involved biological pathways in Cxcl2+ B cells, neutrophils, and inflammatory monocytes are indicated by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and CellChat analysis. In contrast, signaling pathways in the Stmn1+ alveolar macrophages (AMs) and Stmn1– AMs are illustrated by the gene set enrichment analysis. Besides, in the chronic infection condition, expansion of interstitial macrophages and related signaling pathways are shown by the KEGG analysis.
Abstract
The recent advances in spatial transcriptomics have brought unprecedented opportunities to understand the cellular heterogeneity in the spatial context. However, the current limitations of ...spatial technologies hamper the exploration of cellular localizations and interactions at single-cell level. Here, we present spatial transcriptomics deconvolution by topic modeling (STRIDE), a computational method to decompose cell types from spatial mixtures by leveraging topic profiles trained from single-cell transcriptomics. STRIDE accurately estimated the cell-type proportions and showed balanced specificity and sensitivity compared to existing methods. We demonstrated STRIDE’s utility by applying it to different spatial platforms and biological systems. Deconvolution by STRIDE not only mapped rare cell types to spatial locations but also improved the identification of spatially localized genes and domains. Moreover, topics discovered by STRIDE were associated with cell-type-specific functions and could be further used to integrate successive sections and reconstruct the three-dimensional architecture of tissues. Taken together, STRIDE is a versatile and extensible tool for integrated analysis of spatial and single-cell transcriptomics and is publicly available at https://github.com/wanglabtongji/STRIDE.
Oral squamous cell carcinoma (OSCC) is a leading malignancy worldwide; the overall 5-year survival rate is approximately 50%. A variety of proteins in Toll-like receptors (TLRs) pathway have been ...related with the risk of OSCC. However, the influence of genetic variations in TLRs pathway genes on OSCC susceptibility is unclear. Previous studies mainly focused on the coding region of genes, while the UTR region remains unstudied. In the current study, a bioinformatics approach was performed to select candidate single nucleotide polymorphisms (SNPs) on microRNA binding sites of TLRs pathway genes related with OSCC. After screening 90 OSCC related TLRs pathway genes, 16 SNPs were selected for genotyping. We found that rs5030486, the polymorphisms on 3' UTR of TRAF6, was significantly associated with OSCC risk. AG genotype of TRAF6 was strongly associated with a decreased risk of OSCC (OR = 0.252; 95% CI = 0.106, 0.598; p = 0.001). In addition, AG genotype was also related with a reduced risk of OSCC progression both in univariable analysis (HR = 0.303, 95% CI = 0.092, 0.995) and multivariable analysis (HR = 0.272, 95% CI = 0.082, 0.903). Furthermore, after detecting the mRNA expression level of TRAF6 in 24 OSCC patients, we found that TRAF6 expression level was significantly different between patients carrying different genotypes at locus rs5030486 (p = 0.013), indicating that rs5030486 of TRAF6 might contribute to OSCC risk by altering TRAF6 expression level. In general, these data indicated that SNP rs5030486 could be a potential bio-marker for OSCC risk and our results might provide new insights into the association of polymorphisms within the non-coding area of genes with cancers.
The Tumor Immune Single Cell Hub 2 (TISCH2) is a resource of single-cell RNA-seq (scRNA-seq) data from human and mouse tumors, which enables comprehensive characterization of gene expression in the ...tumor microenvironment (TME) across multiple cancer types. As an increasing number of datasets are generated in the public domain, in this update, TISCH2 has included 190 tumor scRNA-seq datasets covering 6 million cells in 50 cancer types, with 110 newly collected datasets and almost tripling the number of cells compared with the previous release. Furthermore, TISCH2 includes several new functions that allow users to better utilize the large-scale scRNA-seq datasets. First, in the Dataset module, TISCH2 provides the cell-cell communication results in each dataset, facilitating the analyses of interacted cell types and the discovery of significant ligand-receptor pairs between cell types. TISCH2 also includes the transcription factor analyses for each dataset and visualization of the top enriched transcription factors of each cell type. Second, in the Gene module, TISCH2 adds functions for identifying correlated genes and providing survival information for the input genes. In summary, TISCH2 is a user-friendly, up-to-date and well-maintained data resource for gene expression analyses in the TME. TISCH2 is freely available at http://tisch.comp-genomics.org/.
PDF
