Identifying Comprehensive Genomic Alterations and Potential Neoantigens for Cervical Cancer Immunotherapy in a Cohort of Chinese Squamous Cell Carcinoma of the Cervix.

Objective: Genomic alterations and potential neoantigens for cervical cancer immunotherapy were identified in a cohort of Chinese patients with cervical squamous cell carcinoma (CSCC). Methods: Whole-exome sequencing was used to identify genomic alterations and potential neoantigens for CSCC immunotherapy. RNA Sequencing was performed to analyze neoantigen expression. Results: Systematic bioinformatics analysis showed that C>T/G>A transitions/transversions were dominant in CSCCs. Missense mutations were the most frequent types of somatic mutation in the coding sequence regions. Mutational signature analysis detected signature 2, signature 6, and signature 7 in CSCC samples. PIK3CA, FBXW7, and BICRA were identified as potential driver genes, with BICRA as a newly reported gene. Genomic variation profiling identified 4,960 potential neoantigens, of which 114 were listed in two neoantigen-related databases. Conclusion: The present findings contribute to our understanding of the genomic characteristics of CSCC and provide a foundation for the development of new biotechnology methods for individualized immunotherapy in CSCC.

The impact of the tumor immune microenvironment and tumor-infiltrating lymphocyte subgroups on laryngeal cancer prognosis.

The absence of improvement in survival rates across various cancers, including laryngeal cancer, has led to an increasing interest in understanding the immune response to cancer. In head and neck cancers, immune modulatory mechanisms such as immune microenvironment and immune infiltration are important in cancer pathogenesis. This study aims to explore the distribution of tumor-infiltrating lymphocyte (TIL) subgroups in the immune microenvironment and evaluate their impact on tumor histopathological characteristics and prognosis. The study included 50 patients who underwent laryngectomy for laryngeal squamous cell carcinoma, in Istanbul University - Cerrahpasa, Faculty of Medicine Department of Otorhinolaryngology, between January 2016 and January 2018. Pathology specimens were evaluated using immunohistochemistry to assess the expressions of the CD3, CD20, CD8, CD4, CD25, and FoxP3 markers, identifying subgroups of TILs. The investigation aimed to uncover how these subgroups influence tumor histopathological features and survival outcomes. The high infiltration of CD3, CD20, and CD4 had a positive impact on disease-specific survival, disease-free survival, and recurrence-free survival. In addition, overall survival was positively affected by high CD3 and CD4 infiltrations. However, no significant relationship was observed between the expressions of CD8, FoxP3, and CD25 and any of the survival parameters. The infiltration of CD3, CD20, and CD4 positive cells indicative of a robust antitumoral immune response-emerged as favorable prognostic factors in laryngeal cancer. These findings suggest that enhancing the infiltration of CD3, CD20, and CD4 lymphocytes could be a therapeutic strategy worth exploring in clinical trials.

Guanylate binding protein 5 is an immune-related biomarker of oral squamous cell carcinoma: A retrospective prognostic study with bioinformatic analysis.

BACKGROUND: Cancer utilizes immunosuppressive mechanisms to create a tumor microenvironment favorable for its progression. The purpose of this study is to histologically characterize the immunological properties of the tumor microenvironment of oral squamous cell carcinoma (OSCC) and identify key molecules involved in the immunological microenvironment and patient prognosis. METHODS: First, overlapping differentially expressed genes (DEGs) were screened from OSCC transcriptome data in public databases. Correlation analysis of DEGs with known immune-related genes identified genes involved in the immune microenvironment of OSCC. Next, stromal patterns of tumor were classified and immunohistochemical staining was performed for immune cell markers (CD3, CD4, Foxp3, CD8, CD20, CD68, and CD163), programmed death-ligand 1 (PD-L1), and guanylate binding protein 5 (GBP5) in resected specimens obtained from 110 patients with OSCC who underwent resection. Correlations between each factor and their prognostic impact were analyzed. RESULTS: Among the novel OSCC-specific immune-related genes screened (including ADAMDEC1, CXCL9, CXCL13, DPT, GBP5, IDO1, and PLA2G7), GBP5 was selected as the target gene. Histopathologic analysis showed that multiple T-cell subsets and CD20-positive cells were less common in the advanced stages, whereas CD163-positive cells were more common in advanced stages. The immature type in the stromal pattern category was associated with less immune cell infiltration, lower expression of PD-L1 in immune cells, lower expression of GBP5 in the stroma, and shorter overall survival and recurrence-free survival. Expression of GBP5 in the tumor and stroma correlated with immune cell infiltration of tumors and PD-L1 expression in tumor and immune cells. Patients with low tumor GBP5 expression and high stromal expression had significantly longer overall survival and recurrence-free survival. CONCLUSIONS: The stromal pattern category may reflect both invasive and immunomodulatory potentials of cancer-associated fibroblasts in OSCC. GBP5 has been suggested as a potential biomarker to predict the prognosis and therapeutic efficacy of immune checkpoint inhibitors.

Novel vaccination strategies based on optimal stimulation of CD4+ T helper cells for the treatment of oral squamous cell carcinoma.

Oral Squamous Cell Carcinoma (OSCC) is the most common malignant tumor of the oral cavity. Despite recent advances in the field of oral cancer therapy, including the introduction of immunotherapeutic approaches, the 5-year survival rate remains steadily assessed around 50%. Thus, there is an urgent need for new therapeutic strategies. After the characterization of the immune phenotype of three human OSCC cell lines (CAL-27, SCC-25, and SCC-4) and one mouse OSCC cell line (MOC2) showing their similarities to resected patient tumors, we explored for the first time an experimental preclinical model of therapeutic vaccination with mouse OSCC MOC2 cell line stably expressing MHC class II antigens after CIITA gene transfection (MOC2-CIITA). Mice injected with MOC2-CIITA reject or strongly retard tumor growth; more importantly, vaccinated animals that fully reject MOC2-CIITA tumors display anti-tumor immunological memory protective against challenge with parental MOC2 tumor cells. Further experiments of adoptive cell transfer or in vivo cell depletion show that both CD4+ and CD8+ T lymphocytes prove fundamental in tumor rejection. This unprecedented approach for oral cancer opens the way for possible future translation of novel immunotherapeutic strategies to the human setting for the treatment of this tumor.

High expression of PD-L1 on conventional dendritic cells in tumour-draining lymph nodes is associated with poor prognosis in oral cancer.

INTRODUCTION: Oral squamous cell carcinoma (OSCC), while common and with a favorable prognosis in early stages, presents a marked reduction in survival rate upon metastasis to lymph nodes. Early detection of lymph node metastasis via biomarkers could enhance the therapeutic strategy for OSCC. Here, we explored dendritic cells (DCs) and cytotoxic T-cells in tumour-draining lymph nodes (TDLNs) as potential biomarkers. METHOD: Dendritic cells and cytotoxic T-cells in 33 lymph nodes were analyzed with multi-parameter flow cytometry in TDLNs, regional non-TDLNs surgically excised from 12 OSCC patients, and compared to 9 lymph nodes from patients with benign conditions. RESULTS: Our results displayed a higher proportion of conventional cDC1s with immunosuppressive features in TDLN. Further, high PD-L1 expression on cDC1 in TDLNs was associated with metastasis and/or recurrent disease risk. Also, elevated levels of memory CD8+ T-cells and terminally exhausted PD-1+TCF-1-CD8+ T-cells were observed in TDLNs and non-TDLNs compared to healthy lymph nodes. CONCLUSIONS: We conclude that TDLNs contain cells that could trigger an anti-tumor adaptive response, as evidenced by activated cDC1s and progenitor-like TCF-1+ T-cells. The detection of high PDL1 expression on cDC1s was indicative of TDLN metastasis and an adverse prognosis, proposing that PD-L1 on dendritic cells in TDLN could serve as a predictive biomarker of OSCC patients with a worse prognosis.

Expression and analysis of CX3CL1 chemokine and CD57+ lymphocytes in oral squamous cell carcinoma and their correlation with clinicopathologic features.

INTRODUCTION: CX3CL1 exhibits chemoattraction for T-cells, monocytes, and CD57+ natural killer cells mediating antitumor immunity. The role of CX3CL1 has been studied in tumors of the breast, lung, colon, pancreas, prostate, etc. The current study was undertaken to understand the importance of CX3CL1 and its correlation with CD57+ cells in oral squamous cell carcinoma (OSCC). MATERIAL AND METHODS: Seventy-five primary OSCC were staged and histopathologically graded, followed by immunohistochemistry for CX3CL1 and CD57. Mann-Whitney U-test, Kruskal-Wallis test, Post hoc Bonferroni test, and Pearson's correlation coefficient were applied. RESULTS: CX3CL1 assessment within the tumor cells was high in 62.66% of cases, and the CD57 Labeling Index (LI) varied over a wide range of 8.2-111.6. A statistically significant reduction in expression of both CX3CL1 and CD57 was observed with an increase in histologic grade (p = 0.021 and 0.038, respectively). DISCUSSION: It is concluded that CX3CL1 and CD57 may be important players in the immune surveillance of OSCC. Further studies with detailed follow-up for the overall survival of patients will help in studying the diagnostic, prognostic, and therapeutic roles of CX3CL1 in OSCC.

Causal association between skin cancer and immune cells: mendelian randomization (MR) study.

BACKGROUND: Numerous meta-analyses and clinical studies have shown that subtypes of immune cells are associated with the development of skin cancer, but it is not clear whether this association is causal or biased. Mendelian randomization (MR) analysis reduces the effect of confounding factors and improves the accuracy of the results when compared to traditional studies. Thus, in order to examine the causal relationship between various immune cell and skin cancer, this study employs two-sample MR. METHODS: This study assesses the causal association between 731 immune cell characteristics and skin cancer using a two-sample Mendel randomization (MR) methodology. Multiple MR methods were used to bias and to derive reliable estimates of causality between instrumental variables and outcomes. Comprehensive sensitivity analyses were used to validate the stability, heterogeneity and horizontal multiplicity of the results. RESULTS: We discovered that potential causal relationships between different types of immune cells and skin cancer disease. Specifically, one type of immune cell as potentially causal to malignant melanoma of skin (MM), eight different types of immune cells as potentially causal to basal cell carcinoma (BCC), four different types of immune cells as potentially causal to actinic keratosis (AK), and no different types of immune cells were found to have a potential causal association with squamous cell carcinoma(SCC), with stability in all of the results. CONCLUSION: This study demonstrates the close connection between immune cells and skin cancer disease by genetic means, which enriches the current knowledge about the role of immune cells in skin cancer and also contributes to the design of therapeutic strategies from an immunological perspective.

The causal relationship between immune cells mediating FIT3L, CCL4, OSM, and skin-derived deteriorated tumors.

OBJECTIVE: Observational studies have identified a dual effect of circulating inflammatory proteins and immune cells on cancer progression. However, the specific mechanisms of action have not been clarified in the exacerbation of cutaneous-origin tumors. Therefore, this study aims to investigate whether the causal relationship between circulating inflammatory factors and basal cell carcinoma (BCC), cutaneous malignant melanoma (SKCM), and cutaneous squamous cell carcinoma (cSCC) is regulated by immune cells. METHODS: This study employed the Two-Sample Mendelian Randomization (TSMR) approach to investigate the causal relationships between 91 circulating inflammatory factors and three prevalent types of skin cancer from a genetic perspective. Bayesian Weighted Mendelian Randomization (BWMR) was also used to validate correlation and reverse MR to assess inverse relationships. Subsequent sensitivity analyses were conducted to limit the impact of heterogeneity and pleiotropy. Finally, the two-step Mendelian Randomization (two-step MR) method was utilized to ascertain the mediating effects of specific immune cell traits in the causal pathways linking circulating inflammatory factors with BCC, SKCM, and cSCC. RESULTS: The Inverse Variance Weighted (IVW) method and the Bayesian Weighted Algorithm collectively identified nine inflammatory factors causally associated with BCC, SKCM, and cSCC. The results from Cochran's Q test, mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger intercept were not statistically significant (p < 0.05). Additionally, the proportions mediated by CD4+ CD8dim T cell %leukocyte, CD4-CD8-Natural Killer T %T cell, and CD20 on IgD-CD38-B cell for FIt3L, CCL4, and OSM were 9.26%, 8.96%, and 10.16%, respectively. CONCLUSION: Immune cell levels potentially play a role in the modulation process between circulating inflammatory proteins and cutaneous-origin exacerbated tumors. This finding offers a new perspective for the in-depth exploration of cutaneous malignancies.

Monocyte infiltration is an independent positive prognostic biomarker in vulvar squamous cell carcinoma.

BACKGROUND: Vulvar squamous cell carcinoma (VSCC) arises after an HPV infection or the mutation of p53 or other driver genes and is treated by mutilating surgery and/or (chemo) radiation, with limited success and high morbidity. In-depth information on the immunological make up of VSCC is pivotal to assess whether immunotherapy may form an alternative treatment. METHODS: A total of 104 patient samples, comprising healthy vulva (n = 27) and VSCC (n = 77), were analyzed. Multispectral immunofluorescence (15 markers) was used to study both the myeloid and lymphoid immune cell composition, and this was linked to differences in transcriptomics (NanoString nCounter, 1258 genes) and in survival (Kaplan-Meier analyses). RESULTS: Healthy vulva and VSCC are both well infiltrated but with different subpopulations of lymphoid and myeloid cells. In contrast to the lymphoid cell infiltrate, the density and composition of the myeloid cell infiltrate strongly differed per VSCC molecular subtype. A relative strong infiltration with epithelial monocytes (HLADR-CD11c-CD14+CD68-CD163-CD33-) was prognostic for improved survival, independent of T cell infiltration, disease stage or molecular subtype. A strong infiltration with T cells and/or monocytes was associated with drastic superior survival: 5-year survival > 90% when either one is high, versus 40% when both are low (p < 0.001). CONCLUSION: A hot myeloid and/or lymphoid infiltrate predicts excellent survival in VSCC. Based on the response of similarly high-infiltrated other tumor types, we have started to explore the potential of neoadjuvant checkpoint blockade in VSCC.

FAM20A: a potential diagnostic biomarker for lung squamous cell carcinoma.

Background: Lung squamous cell carcinoma (LUSC) ranks among the carcinomas with the highest incidence and dismal survival rates, suffering from a lack of effective therapeutic strategies. Consequently, biomarkers facilitating early diagnosis of LUSC could significantly enhance patient survival. This study aims to identify novel biomarkers for LUSC. Methods: Utilizing the TCGA, GTEx, and CGGA databases, we focused on the gene encoding Family with Sequence Similarity 20, Member A (FAM20A) across various cancers. We then corroborated these bioinformatic predictions with clinical samples. A range of analytical tools, including Kaplan-Meier, MethSurv database, Wilcoxon rank-sum, Kruskal-Wallis tests, Gene Set Enrichment Analysis, and TIMER database, were employed to assess the diagnostic and prognostic value of FAM20A in LUSC. These tools also helped evaluate immune cell infiltration, immune checkpoint genes, DNA repair-related genes, DNA methylation, and tumor-related pathways. Results: FAM20A expression was found to be significantly reduced in LUSC, correlating with lower survival rates. It exhibited a negative correlation with key proteins in DNA repair signaling pathways, potentially contributing to LUSC's radiotherapy resistance. Additionally, FAM20A showed a positive correlation with immune checkpoints like CTLA-4, indicating potential heightened sensitivity to immunotherapies targeting these checkpoints. Conclusion: FAM20A emerges as a promising diagnostic and prognostic biomarker for LUSC, offering potential clinical applications.

Tumor-Infiltrating T Cells in Skin Basal Cell Carcinomas and Squamous Cell Carcinomas: Global Th1 Preponderance with Th17 Enrichment-A Cross-Sectional Study.

Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are high-incidence, non-melanoma skin cancers (NMSCs). The success of immune-targeted therapies in advanced NMSCs led us to anticipate that NMSCs harbored significant populations of tumor-infiltrating lymphocytes with potential anti-tumor activity. The main aim of this study was to characterize T cells infiltrating NMSCs. Flow cytometry and immunohistochemistry were used to assess, respectively, the proportions and densities of T cell subpopulations in BCCs (n = 118), SCCs (n = 33), and normal skin (NS, n = 30). CD8+ T cells, CD4+ T cell subsets, namely, Th1, Th2, Th17, Th9, and regulatory T cells (Tregs), CD8+ and CD4+ memory T cells, and γδ T cells were compared between NMSCs and NS samples. Remarkably, both BCCs and SCCs featured a significantly higher Th1/Th2 ratio (~four-fold) and an enrichment for Th17 cells. NMSCs also showed a significant enrichment for IFN-γ-producing CD8+T cells, and a depletion of γδ T cells. Using immunohistochemistry, NMSCs featured denser T cell infiltrates (CD4+, CD8+, and Tregs) than NS. Overall, these data favor a Th1-predominant response in BCCs and SCCs, providing support for immune-based treatments in NMSCs. Th17-mediated inflammation may play a role in the progression of NMSCs and thus become a potential therapeutic target in NMSCs.

Unraveling Differences in Molecular Mechanisms and Immunological Contrasts between Squamous Cell Carcinoma and Adenocarcinoma of the Cervix.

This study aims to refine our understanding of the inherent heterogeneity in cervical cancer by exploring differential gene expression profiles, immune cell infiltration dynamics, and implicated signaling pathways in the two predominant histological types of cervix carcinoma, Squamous Cell Carcinoma (SCC) and Adenocarcinoma (ADC). Targeted gene expression data that were previously generated from samples of primary cervical cancer were re-analyzed. The samples were grouped based on their histopathology, comparing SCC to ADC. Each tumor in the study was confirmed to be high risk human papilloma virus (hrHPV) positive. A total of 21 cervical cancer samples were included, with 11 cases of SCC and 10 of ADC. Data analysis revealed a total of 26 differentially expressed genes, with 19 genes being overexpressed in SCC compared to ADC (Benjamini-Hochberg (BH)-adjusted p-value < 0.05). Importantly, the immune checkpoint markers CD274 and CTLA4 demonstrated significantly higher expression in SCC compared to ADC. In addition, SCC showed a higher infiltration of immune cells, including B and T cells, and cytotoxic cells. Higher activation of a variety of pathways was found in SCC samples including cytotoxicity, interferon signaling, metabolic stress, lymphoid compartment, hypoxia, PI3k-AKT, hedgehog signaling and Notch signaling pathways. Our findings show distinctive gene expression patterns, signaling pathway activations, and trends in immune cell infiltration between SCC and ADC in cervical cancer. This study underscores the heterogeneity within primary cervical cancer, emphasizing the potential benefits of subdividing these tumours based on histological and molecular differences.

The Immune Checkpoint BTLA in Oral Cancer: Expression Analysis and Its Correlation to Other Immune Modulators.

In oral squamous cell carcinoma (OSCC) tissues, an immunotolerant situation triggered by immune checkpoints (ICPs) can be observed. Immune checkpoint inhibitors (ICIs) against the PD1/PD-L axis are used with impressive success. However, the response rate is low and the development of acquired resistance to ICI treatment can be observed. Therefore, new treatment strategies especially involving immunological combination therapies need to be developed. The novel negative immune checkpoint BTLA has been suggested as a potential biomarker and target for antibody-based immunotherapy. Moreover, improved response rates could be displayed for tumor patients when antibodies directed against BTLA were used in combination with anti-PD1/PD-L1 therapies. The aim of the study was to check whether the immune checkpoint BTLA is overexpressed in OSCC tissues compared to healthy oral mucosa (NOM) and could be a potential diagnostic biomarker and immunological target in OSCC. In addition, correlation analyses with the expression of other checkpoints should clarify more precisely whether combination therapies are potentially useful for the treatment of OSCC. A total of 207 tissue samples divided into 2 groups were included in the study. The test group comprised 102 tissue samples of OSCC. Oral mucosal tissue from 105 healthy volunteers (NOM) served as the control group. The expression of two isoforms of BTLA (BTLA-1/2), as well as PD1, PD-L1/2 and CD96 was analyzed by RT-qPCR. Additionally, BTLA and CD96 proteins were detected by IHC. Expression levels were compared between the two groups, the relative differences were calculated, and statistical relevance was determined. Furthermore, the expression rates of the immune checkpoints were correlated to each other. BTLA expression was significantly increased in OSCC compared to NOM (pBTLA_1 = 0.003; pBTLA_2 = 0.0001, pIHC = 0.003). The expression of PD1, its ligands PD-L1 and PD-L2, as well as CD96, were also significantly increased in OSCC (p ≤ 0.001). There was a strong positive correlation between BTLA expression and that of the other checkpoints (p < 0.001; ρ ≥ 0.5). BTLA is overexpressed in OSCC and appears to be a relevant local immune checkpoint in OSCC. Thus, antibodies directed against BTLA could be potential candidates for immunotherapies, especially in combination with ICI against the PD1/PD-L axis and CD96.

Stabilization of EREG via STT3B-mediated N-glycosylation is critical for PDL1 upregulation and immune evasion in head and neck squamous cell carcinoma.

Dysregulated Epiregulin (EREG) can activate epidermal growth factor receptor (EGFR) and promote tumor progression in head and neck squamous cell carcinoma (HNSCC). However, the mechanisms underlying EREG dysregulation remain largely unknown. Here, we showed that dysregulated EREG was highly associated with enhanced PDL1 in HNSCC tissues. Treatment of HNSCC cells with EREG resulted in upregulated PDL1 via the c-myc pathway. Of note, we found that N-glycosylation of EREG was essential for its stability, membrane location, biological function, and upregulation of its downstream target PDL1 in HNSCC. EREG was glycosylated at N47 via STT3B glycosyltransferases, whereas mutations at N47 site abrogated N-glycosylation and destabilized EREG. Consistently, knockdown of STT3B suppressed glycosylated EREG and inhibited PDL1 in HNSCC cells. Moreover, treatment of HNSCC cells with NGI-1, an inhibitor of STT3B, blocked STT3B-mediated glycosylation of EREG, leading to its degradation and suppression of PDL1. Finally, combination of NGI-1 treatment with anti-PDLl therapy synergistically enhanced the efficacy of immunotherapy of HNSCC in vivo. Taken together, STT3B-mediated N-glycosylation is essential for stabilization of EREG, which mediates PDL1 upregulation and immune evasion in HNSCC.

Cancer cell plasticity defines response to immunotherapy in cutaneous squamous cell carcinoma.

Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC) patients remain unresponsive or develop resistance. Here, we show that, during cSCC progression in male mice, cancer cells acquire epithelial/mesenchymal plasticity and change their immune checkpoint (IC) ligand profile according to their features, dictating the IC pathways involved in immune evasion. Epithelial cancer cells, through the PD-1/PD-L1 pathway, and mesenchymal cancer cells, through the CTLA-4/CD80 and TIGIT/CD155 pathways, differentially block antitumor immune responses and determine the response to ICB therapies. Accordingly, the anti-PD-L1/TIGIT combination is the most effective strategy for blocking the growth of cSCCs that contain both epithelial and mesenchymal cancer cells. The expression of E-cadherin/Vimentin/CD80/CD155 proteins in cSCC, HNSCC and melanoma patient samples predicts response to anti-PD-1/PD-L1 therapy. Collectively, our findings indicate that the selection of ICB therapies should take into account the epithelial/mesenchymal features of cancer cells.

Prognostic Role of Tumor-Infiltrating Lymphocytes in Oral Squamous Cell Carcinoma.

BACKGROUND: In oral squamous cell carcinoma (OSCC), the tumor-node-metastasis (TNM) staging system is a significant factor that influences prognosis and treatment decisions for OSCC patients. Unfortunately, TNM staging does not consistently predict patient prognosis and patients with identical clinicopathological characteristics may have vastly different survival outcomes. Host immunity plays an important role in tumor progression but is not included in the TNM staging system. Tumor-infiltrating lymphocytes (TILs) are part of the host immune response that recognizes tumor cells; and the presence of TILs has emerged as potential candidates for prognostic markers for many types of cancers. The present study aims to determine the association of T cell-specific markers (CD3, CD4, CD8, and FOXP3) with clinicopathological characteristics and survival outcomes in OSCC patients. The prognostic value of CD3, CD4, and CD8 will also be evaluated based on tumor stage. METHODS: Tissue microarrays were constructed containing 231 OSCC cases and analyzed by immunohistochemical staining for the expression of CD3, CD4, CD8, and FOXP3. The expression scores for each marker were correlated with clinicopathological parameters and survival outcomes. The prognostic impact of CD3, CD4 and CD8 were further analyzed based on tumor stage (early or advanced). RESULTS: CD3, CD4, and CD8 were found to be significantly associated with both overall survival and progression-free survival using univariate analysis. However, none of these markers were found to independently predict the survival outcomes of OSCC using multivariate analysis. Only conventional factors such as nodal status, tumor differentiation and perineural invasion (PNI) were independent predictors of survival outcomes, with nodal status being the strongest independent predictor. Additionally, low CD4 (but not CD3 or CD8) expression was found to identify early-stage OSCC patients with exceptionally poor prognosis which was similar to that of advanced staged OSCC patients. CONCLUSIONS: TIL markers such as CD3, CD4, CD8, and FOXP3 can predict the survival outcomes of OSCC patients, but do not serve as independent prognostic markers as found with conventional factors (i.e. nodal status, tumor differentiation and PNI). CD4 expression may assist with risk stratification in early-stage OSCC patients which may influence treatment planning and decision making for early-stage OSCC patients.

Low densities of immune cells indicate unfavourable overall survival in patients suffering from squamous cell carcinoma of the lung.

Carcinogenesis and tumor proliferation are characterized by a complex interaction of cancer cells with the tumor microenvironment. In particular, a tumor-promoting effect can be assumed for the stroma and its fibroblasts. An influence of the immune system on non small cell lung cancer (NSCLC) is now also suspected. In our study, we examined 309 sections of squamous cell carcinoma (SCC), a subtype of NSCLC. We determined the cell densities and areas of the different tissues in SCC using the software QuPath. Spearman rank correlation showed a significant positive correlation between the different tumor cell densities and stromal cell densities, and between tumor cell densities and immune cell densities. Overall survival curves by the Kaplan-Meier method revealed a prominent negative curve in cases of low immune cell density. Based on our results, we can assume a positive influence of the tumor microenvironment, especially the stromal cells, on tumor proliferation in SCC. We have also revealed that low density of immune cells is prognostically unfavorable.

Integrated bioinformatics combined with machine learning to analyze shared biomarkers and pathways in psoriasis and cervical squamous cell carcinoma.

Background: Psoriasis extends beyond its dermatological inflammatory manifestations, encompassing systemic inflammation. Existing studies have indicated a potential risk of cervical cancer among patients with psoriasis, suggesting a potential mechanism of co-morbidity. This study aims to explore the key genes, pathways, and immune cells that may link psoriasis and cervical squamous cell carcinoma (CESC). Methods: The cervical squamous cell carcinoma dataset (GSE63514) was downloaded from the Gene Expression Omnibus (GEO). Two psoriasis-related datasets (GSE13355 and GSE14905) were merged into one comprehensive dataset after removing batch effects. Differentially expressed genes were identified using Limma and co-expression network analysis (WGCNA), and machine learning random forest algorithm (RF) was used to screen the hub genes. We analyzed relevant gene enrichment pathways using GO and KEGG, and immune cell infiltration in psoriasis and CESC samples using CIBERSORT. The miRNA-mRNA and TFs-mRNA regulatory networks were then constructed using Cytoscape, and the biomarkers for psoriasis and CESC were determined. Potential drug targets were obtained from the cMAP database, and biomarker expression levels in hela and psoriatic cell models were quantified by RT-qPCR. Results: In this study, we identified 27 key genes associated with psoriasis and cervical squamous cell carcinoma. NCAPH, UHRF1, CDCA2, CENPN and MELK were identified as hub genes using the Random Forest machine learning algorithm. Chromosome mitotic region segregation, nucleotide binding and DNA methylation are the major enrichment pathways for common DEGs in the mitotic cell cycle. Then we analyzed immune cell infiltration in psoriasis and cervical squamous cell carcinoma samples using CIBERSORT. Meanwhile, we used the cMAP database to identify ten small molecule compounds that interact with the central gene as drug candidates for treatment. By analyzing miRNA-mRNA and TFs-mRNA regulatory networks, we identified three miRNAs and nine transcription factors closely associated with five key genes and validated their expression in external validation datasets and clinical samples. Finally, we examined the diagnostic effects with ROC curves, and performed experimental validation in hela and psoriatic cell models. Conclusions: We identified five biomarkers, NCAPH, UHRF1, CDCA2, CENPN, and MELK, which may play important roles in the common pathogenesis of psoriasis and cervical squamous cell carcinoma, furthermore predict potential therapeutic agents. These findings open up new perspectives for the diagnosis and treatment of psoriasis and squamous cell carcinoma of the cervix.