Tumor-infiltrating Immune Cells Research Articles

Unraveling the role of interferon-stimulated neutrophils: A promising biomarker for immunotherapy efficacy and prognosis in gastric adenocarcinoma.

472 Background: Despite significant advancements in immunotherapy, the identification of effective predictive biomarkers for treatment response in gastric adenocarcinoma (GAC) remains a critical challenge. Discovering such biomarkers could enhance patient stratification and improve therapeutic outcomes. Methods: We conducted a comprehensive analysis of 18 specimens obtained from 10 GAC patients, both prior to and following immunotherapy. Utilizing single-cell RNA sequencing, we compared the cellular composition and functional phenotypes of these specimens, with particular emphasis on tumor-infiltrating immune cells and the identification of previously uncharacterized neutrophil subclusters. Results: Our analysis identified eight distinct neutrophil subclusters, including Neu01_S100A12, Neu02_VEGF, Neu03_CCL3_CCL4, Neu04_IL1β, Neu05_CXCR4, Neu06_IFN-Stimulated, Neu07_Proliferative, and Neu08_B-cell_related. Notably, the presence of IFN-Stimulated neutrophils was positively correlated with the efficacy of immunotherapy in GAC, a finding that was further validated through analyses of public datasets and in-house cohort studies employing multiplex immunohistochemistry. Additionally, IFN-Stimulated neutrophils served as prognostic indicators across multiple datasets. Investigations revealed that these cells engage in significant cellular communication with other immune components within the tumor microenvironment, including CD8+ T cells, macrophages, and B cells, thereby promoting a pro-inflammatory and anti-tumor phenotype. Importantly, pan-cancer analyses demonstrated the consistent prognostic and immunotherapy efficacy-predicting potential of IFN-Stimulated neutrophils across various cancer types. Conclusions: IFN-Stimulated neutrophils represent a promising biomarker for predicting immunotherapy response and patient prognosis in GAC. Our findings offer novel insights into the underlying mechanisms of immunotherapy and highlight potential avenues for personalized treatment strategies in the management of GAC.

Efficacy of Second-line Nivolumab Versus Tyrosine Kinase Inhibitors for Renal Cell Carcinoma With Bone Metastases.

Combination therapy with immune checkpoint inhibitors has become the standard first-line treatment for metastatic renal cell carcinoma (mRCC), leading to changes in second-line treatment options, such as nivolumab or tyrosine kinase inhibitors (TKIs). However, very few studies have compared the efficacy of these drugs in patients with mRCC, particularly those with bone metastases (BM), which are associated with a poor prognosis. This study compared the efficacy of nivolumab and TKIs as second-line treatments for mRCC patients with BM and examined the microenvironments of primary tumors and BM lesions. This multi-institutional retrospective study included 87 mRCC patients with BM who received either nivolumab or TKIs as second-line treatments. We analyzed tumor-infiltrating immune cells expressing CD8 and CD20, along with PD-L1, HIF2α, c-MET, VEGFR2, and AXL, in primary tumors and BM sites using immunohistochemistry. This analysis indicated that poor-risk classification, as per the International Metastatic RCC Database Consortium criteria (p<0.01), and elevated serum alkaline phosphatase levels (p=0.031) were significantly associated with poor prognosis. No significant difference in overall survival was observed between patients receiving nivolumab and those receiving TKIs. However, the objective response rate of patients with BM lesions was significantly higher when receiving TKIs than when receiving nivolumab (p=0.014). Immunohistochemistry revealed significantly higher VEGFR2 expression in BM lesions than primary tumors. TKIs could be a promising second-line treatment option for mRCC patients with bone-limited metastases.

The Gastric Cancer Registry: A multi-omic cellular and molecular resource for cancer biomarker and therapeutic discovery.

491 Background: The Gastric Cancer Registry (GCR) is a comprehensive clinical and genomic data resource focused on gastric cancer (GC) patients and individuals with a family history of GC or a germline CDH1 mutation. As part of the GCR’s ongoing enrollment, patients contribute cancer history information, archival tumor samples and other biospecimens. The cancer samples undergo extensive molecular and cellular analysis that includes genomic sequencing and spatial analysis. We have generated a robust dataset, publicly accessible online through the GCR Genome Explorer (GCR-GE). This genomic, molecular and cellular resource provides a rich data set that accelerates multidisciplinary research aimed at improving detection and treatment strategies for GC. GC disproportionately affects Latin American populations - we have included new cohorts from Latin America. The GCR enables researchers, clinicians and patients to address specific questions about the molecular and cellular basis of GC. Methods: GC samples underwent whole genome, whole exome, and bulk RNA sequencing were conducted. The genomic features identified include copy number variation, gene mutations, gene expression, microbiome composition, estimation of tumor-infiltrating immune cells, tumor neoantigens, MSI/MSS status, and HLA subtypes. In addition to genomic data, clinical data was compiled from survey responses and pathology reports and integrated into the GCR-GE. We have incorporated single cell and spatial analysis that includes diverse cell types, single cell gene expression and cellular architecture in native tumor tissues. This data was released to the GCR Genome Explorer website. Results: A total of 817 subjects have enrolled in the GCR including 598 diagnosed with GC and 219 at high-risk for GC through family history of GC and/or a CDH1 mutation. Of the 598 with GC, some met multiple criteria including at least 40 with a family history of GC, 10 with a CDH1 mutation, and 18 with both a family history of GC and a CDH1 mutation. The GCR-GE includes data from 257 gastric tumors in addition to external datasets from TCGA. In the latest data release, clinical and genomic data from 78 gastric tumors from patients in Latin America were integrated into the GCR-GE. Conclusions: The GCR is a comprehensive database of crucial clinical and genomic data necessary for driving forward GC research. Through global expansion, the GCR has generated a more representative dataset by increasing racial diversity and including underrepresented populations that are at higher risk for GC.

Immune microenvironment features underlying the superior efficacy of neoadjuvant immunochemotherapy over chemotherapy in local advanced gastric cancer

BackgroundThe therapeutic efficacy of neoadjuvant immunotherapy combined with chemotherapy (Io+Chemo) is superior than chemotherapy alone (Chemo). However, the mechanism of Io+Chemo superiority remains to be further elucidated.MethodsThe study included 128 patients with resectable stage II-III gastric cancer, in which 63 were given neoadjuvant Io+Chemo, and 65 Chemo alone. Patients given Io+Chemo were treated with 2-4 cycles of PD-(L)1 inhibitor (Pembrolizumab, Sintililimab or Nivolumab) with S-1 and oxaliplatin (SOX) or capecitabine and oxaliplatin (XELOX) before surgical resection. Patients given Chemo were treated with 2-4 cycles of SOX or XELOX before surgical resection. Tumor tissues were evaluated for tumor-infiltrating immune cells (TIICs) using immunohistochemistry and QuPath software quantitative analysis, for detecting T, B, NK, plasma cells, and macrophages. The relationship between TIICs and different neoadjuvant treatment regimens and pathological responses was also explored.ResultsCompared with Chemo, Io+Chemo induced higher rates of pathological complete response (33.3 vs. 9.2%, p=0.001) and major pathological response (MPR) (49.2 vs. 30.8%, p=0.033). Compared with Chemo group, density of CD4+(1904.8 vs. 1530), CD8+(1982.9 vs. 1124.4), CD20+(1115.6 vs. 574), CD38+(1580.4 vs. 1128), CD138+(1237.2 vs. 496.4), and CD56+ (596.8 vs. 159) cells was increased 24.5%, 76.4%, 94.4%, 40.1%, and 149.2% respectively, whereas CD163+ macrophages (994.4 vs. 1706) was decreased 41.7% in Io+Chemo group.ConclusionsOur study favors neoadjuvant Io+Chemo over Chemo and reveals Io+Chemo can induce the formation of an immune-activated microenvironment that make Io+Chemo superior to Chemo.

TNIP1 Impacts Prognosis by Modulating the Immune Microenvironment in BRCA.

Breast invasive carcinoma (BRCA) affects women worldwide, and despite advancements in diagnosis, prevention, and treatment, outcomes remain suboptimal. TNIP1, a novel target involved in multiple immune signaling pathways, influences tumor development and survival. However, the connection between BRCA and TNIP1 remains unclear. Analysis of data from the TCGA, GEO, Sangerbox, and Ualcan databases revealed that TNIP1 is underexpressed in BRCA tissues. This finding was corroborated by RT-PCR and immunohistochemistry. Furthermore, data from the TCGA and GEPIA2 databases, along with Sangerbox, identified TNIP1 as a marker of poor prognosis in BRCA patients. TNIP1 expression shows significant positive correlations with the BRCA Tumor Microenvironment (TME) StromalScore (R = 0.22), ImmuneScore (R = 0.25), and ESTIMATEScore (R = 0.27). Various algorithms have demonstrated a strong association between TNIP1 expression and BRCA tumor-infiltrating immune cells (TIICs). Further analysis using EPIC, TIMER, MCPCounter, QUANTISEQ, xCell, and other computational tools revealed that elevated TNIP1 expression is significantly associated with increased immune cell scores. TNIP1 expression in BRCA tumor tissues also shows a strong correlation with immune checkpoint markers. Data from the HAP database indicate that TNIP1 expression is predominantly involved in the normal skin microenvironment. Subsequent analysis using the TISCH platform with the BRCA single-cell dataset demonstrated that TNIP1 exhibits higher expression levels in immune cells compared to non-immune cells in BRCA patients. This expression is significantly positively correlated with inflammation (R = 0.25) and differentiation (R = 0.28) within the TME, while showing negative correlations with BRCA stemness (R = -0.34) and invasion (R = -0.22). Consequently, TNIP1 is proposed as a potential prognostic marker and therapeutic target for BRCA.

A detoxified TLR4 agonist inhibits tumour growth and lung metastasis of osteosarcoma by promoting CD8+ cytotoxic lymphocyte infiltration

BackgroundOsteosarcoma is the most common malignant bone tumour with limited treatment options and poor outcomes in advanced metastatic cases. Current immunotherapies show limited efficacy, highlighting the need for novel therapeutic approaches. Systemic immune activation by Toll-like receptor 4 (TLR4) immunostimulants has shown great promise; however, current TLR4 agonists’ toxicity hinders this systemic approach in patients with osteosarcoma.MethodsWe compared the antitumour effect of lipopolysaccharides (LPS) with that of an innovative chemically detoxified TLR4 agonist (Lipo-MP-LPS) in a syngeneic metastatic osteosarcoma mouse model. Lipo-MP-LPS exhibited an optimal safety and solubility profile for systemic administration at an effective dose. We evaluated tumour growth, lung metastases, and immune cell infiltration in wild-type and TLR4-mutant mice and performed selective immunodepletion.ResultsLipo-MP-LPS exhibited antitumour effects against localised osteosarcoma tumours and lung metastases, like those of natural LPS. Lipo-MP-LPS promoted CD8+ T cells and M1 macrophages infiltration in primary tumours and CD8+ T cells in metastases, with an M1-phenotype macrophage shift. The Lipo-MP-LPS antitumour effects were found to depend on TLR4 and CD8+ T cells, but not on macrophages.ConclusionLipo-MP-LPS inhibited tumour growth and lung metastasis of osteosarcoma by promoting CD8 + T cell infiltration, indicating its therapeutic potential for advanced osteosarcoma.

Antitumor Research Based on Drug Delivery Carriers: Reversing the Polarization of Tumor-Associated Macrophages.

The development of malignant tumors is a complex process that involves the tumor microenvironment (TME). An immunosuppressive TME presents significant challenges to current cancer therapies, serving as a key mechanism through which tumor cells evade immune detection and play a crucial role in tumor progression and metastasis. This impedes the optimal effectiveness of immunotherapeutic approaches, including cytokines, immune checkpoint inhibitors, and cancer vaccines. Tumor-associated macrophages (TAMs), a major component of tumor-infiltrating immune cells, exhibit dual functionalities: M1-like TAMs suppress tumorigenesis, while M2-like TAMs promote tumor growth and metastasis. Consequently, the development of various nanocarriers aimed at polarizing M2-like TAMs to M1-like phenotypes through distinct mechanisms has emerged as a promising therapeutic strategy to inhibit tumor immune escape and enhance antitumor responses. This Review covers the origin and types of TAMs, common pathways regulating macrophage polarization, the role of TAMs in tumor progression, and therapeutic strategies targeting TAMs, aiming to provide a comprehensive understanding and guidance for future research and clinical applications.

Abstract B011: Adenosine signaling and immune modulation in the tumor microenvironment: insights from lung cancer murine model of radiation therapy

Abstract Introduction: Radiation therapy (RT) induces adenosine signaling by releasing ATP in the tumor microenvironment (TME), promoting immune suppression and tumor progression. This study investigates how RT impacts adenosine signaling and immune cell infiltration in a preclinical model of non-small cell lung cancer (NSCLC). Using immunophenotyping of tumor-infiltrating immune cells in LLC1 murine model, we aim to explore the potential of targeting the adenosine pathway in combination with RT to enhance antitumor immunity and clinical outcomes. Methods: LLC1 tumor cells (5 x 105) were implanted subcutaneously in the flanks of C57BL/6 mice. After 12 days, mice received RT (4 Gy x 3 or 8 Gy x 3). Tumor volumes were measured thrice a week and harvested 5- and 10-days post-RT. We performed immunophenotyping of tumor tissue to assess changes in immune (CD45+) and CD45- compartments. The expression of adenosine signaling pathway members was quantified in distinct immune cell populations. Results: RT caused significant inhibition in tumor growth in a dose- and time-dependent manner. 5-days post-RT, CD73 (P&amp;lt; 0.01) and CD39 expressions (P&amp;lt; 0.01) were significantly upregulated in the immune compartment, while A2BR (P&amp;lt; 0.01) and A2AR (P&amp;lt; 0.05) were decreased in the non-immune compartment. RT decreased T cell populations, including CD4+ and CD8+ T cells. Further, CD4+ T cells downregulate adenosine signaling markers, particularly CD73 (P&amp;lt; 0.05) and ENPP1 (P&amp;lt; 0.05), while CD8+ T cells decreased in CD73 expression (P&amp;lt; 0.01). Myeloid subtype abundance was unchanged, but A2AR, A2BR, CD39, and CD73 expressions increased in the M2-like macrophage compartment (F4-80+MHCII-). 10 days post-RT, all adenosine signaling pathway markers significantly increased in the immune compartment and significantly decreased in the non-immune compartment. T cells (TCRb+) and macrophages (F4-80+) increased in abundance, including immuno-suppressive Arg+ macrophages (P&amp;lt; 0.05). Macrophage population that expressed the adenosine signaling markers increased by 10-15% (P&amp;lt; 0.05). While the proportion of CD4+ T cells and Tregs (CD4+FoxP3+) that expressed CD39 and CD73 also increased (P&amp;lt; 0.05). Conclusions: Our study revealed that RT promotes an immunosuppressive TME, in part through adenosine signaling. 5 days post-RT, we observed lymphocyte depletion and upregulation of the adenosine signaling pathway in M2-like macrophages. 10 days post-RT, adenosine signaling significantly increased across the immune compartment and decreased in the non-immune compartment, suggesting that the increase in adenosine signaling post-RT is immunologically mediated and largely driven by the myeloid compartment. These data lead to the hypothesis that inhibition of the adenosine signaling pathway may partially mitigate RT-induced immune suppression and improve RT efficacy. Ongoing work includes quantification of adenosine by LC-MS, extension to a preclinical SCC model of NSCLC, and evaluating adenosine pathway inhibition in combination with RT as a therapeutic strategy to improve antitumor immune responses. Citation Format: Krishan K. Saini, Samanta Sarti, Chelsea L. Rahiman, Brian E. Ragaishis, Patrick J. McCann, Shruti Bansal, Jason Cham, Julia An, Rosa Martin, Ariel Chen, Catherine S. Spina. Adenosine signaling and immune modulation in the tumor microenvironment: insights from lung cancer murine model of radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B011.

Mendelian randomization analysis of the causal association between immune cells and pancreatic cancer

Aims: Pancreatic cancer (PC) is a highly lethal malignancy with limited treatment options. Tumor-infiltrating immune cells have been implicated in the progression and prognosis of PC. However, the causal role of immune cell populations in pancreatic cancer development and progression remains unclear. This study aims to elucidate the causal relationships between specific immune cell populations and the risk of pancreatic cancer, addressing gaps in current understanding. Method: We conducted an extensive two-sample Mendelian randomization (MR) analysis. Using publicly available genetic data, we investigated the causal relationship between 731 immune cells and PC. We used inverse variance weighting (IVW) and weighted medians for MR analyses and used sensitivity analyses to assess heterogeneity and pleiotropy. Results: In terms of the association between immune cells and PC, we found that CD62L- HLA DR++ monocyte % monocytes (OR = 1.1081, 95% CI = 1.0175–1.2068, p = 0.0184), SSC–A on HLA DR+ CD8br (OR = 1.1068, 95% CI = 1.0024-1.2221, p = 0.0448), CD64 on monocytes (OR = 0.8594, 95% CI = 0.8021-0.9207, p 0.001), double-negative (DN) (CD4-CD8-) NKT %T cells (OR = 0.8712, 95% CI = 0.7802-0.9728, p = 0.0143), and SSC–A on HLA DR+ CD4+ cells (OR = 0.8902, 95% CI = 0.8028-0.9870, p = 0.0272) were strongly associated with PC. Among them, CD62L- HLA DR++ monocyte % monocytes and SSC–A on HLA DR+ CD8br are the risk factors, while CD64 on monocytes, DN (CD4-CD8-) NKT %T cells, and SSC–A on HLA DR+ CD4+ cells are protective factors for PC. Conclusion: Our analysis provides evidence for a causal relationship between specific immune cell populations and PC. Targeting immune cell populations with therapeutic interventions such as immunotherapies may hold promise for improving outcomes in PC patients. Further studies are warranted to validate these findings and explore the underlying mechanisms involved in the immune response to PC.

Revolutionizing ESCC prognosis: the efficiency of tumor-infiltrating immune cells (TIIC) signature score

BackgroundPatients suffer from esophageal squamous cell carcinoma (ESCC), which is the ninth highly aggressive malignancy. Tumor-infiltrating immune cells (TIIC) exert as major component of the tumor microenvironment (TME), showing possible prognostic value in ESCC.MethodsTranscriptome data and scRNA-seq data of ESCC samples were extracted from the GEO and TCGA databases. Tissue Specific Index (TSI) was defined to identify potential TIIC-RNAs from the TME. Twenty machine learning algorithms were further applied to evaluate the prognostic efficacy of TIIC signature score. Gene colocalization analysis was performed. Differences in CNV on chromosomes and SNP sites of prognostic model genes were calculated.ResultsThe most reliable model of TIIC signature score was developed based on three prognostic TIIC-RNAs. It showed a higher C-index than any other reported prognostic models. ESCC patients with high TIIC signature score showed poorer survival outcomes than low TIIC signature score. The activity of most immune cells decreased with the increase of TIIC score. TIIC signature score showed difference in the expression levels and methylation levels of DEGs. There was also significant different correlation with the degree of CNV amplification and CNV deletion of the immune checkpoint genes. Gene colocalization analysis showed two prognostic model genes (ATP6V0E1 and BIRC2). MR analysis found that rs148710154 and rs75146099 SNP sites of TIIC-RNA gene had a significant correlation between them gastro-oesophageal reflux and ESCC.ConclusionTIIC signature score was the first time developed which provided a novel strategy and guidance for the prognosis and immunotherapy of ESCC. It also gave the evidence in the important role of immune cells from the TME in the treatment of cancers.

The Single-Cell Landscape of Peripheral and Tumor-infiltrating Immune Cells in HPV- HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. HPV-negative HNSCC, which arises in the upper airway mucosa, is particularly aggressive, with nearly half of patients succumbing to the disease within five years and limited response to immune checkpoint inhibitors compared to other cancers. There is a need to further explore the complex immune landscape in HPV-negative HNSCC to identify potential therapeutic targets. Here, we integrated two single-cell RNA sequencing datasets from 29 samples and nearly 300,000 immune cells to investigate immune cell dynamics across tumor progression and lymph node metastasis. Notable shifts toward adaptative immune cell populations were observed in the 14 distinct HNSCC-associated peripheral blood mononuclear (PBMCs) and 21 tumor-infiltrating immune cells (TICs) considering disease stages. All PBMCs and TICs revealed unique molecular signatures correlating with lymph node involvement; however, broadly, TICs increased ligand expression among effector cytokines, growth factors, and interferon-related genes. Pathway analysis comparing PBMCs and TICs further confirmed active cell signaling among Monocyte-Macrophage, Dendritic cell, Natural Killer (NK), and T cell populations. Receptor-ligand analysis revealed significant communication patterns shifts among TICs, between CD8+ T cells and NK cells, showing heightened immunosuppressive signaling that correlated with disease progression. In locally invasive HPV-negative HNSCC samples, highly multiplexed immunofluorescence assays highlighted peri-tumoral clustering of exhausted CD8+ T and NK cells, alongside their exclusion from intra-tumoral niches. These findings emphasize cytotoxic immune cells as valuable biomarkers and therapeutic targets, shedding light on the mechanisms by which the HNSCC sustainably evades immune responses.

Systems-level immunomonitoring in children with solid tumors to enable precision medicine.

Cancer is the leading cause of death from disease in children. Survival depends not only on surgery, cytostatic drugs, and radiation but also on systemic immune responses. Factors influencing these immune responses in children of different ages and tumor types are unknown. Novel immunotherapies can enhance anti-tumor immune responses, but few children have benefited, and markers of effective responses are lacking. Here, we present a systems-level analysis of immune responses in 191 children within a population-based cohort with diverse tumors and reveal that age and tumor type shape immune responses differently. Systemic inflammation and cytotoxic Tcell responses correlate with tumor mutation rates and immune cell infiltration. Clonally expanded Tcell responses are rarely detected in blood or tumors at diagnosis but are sometimes elicited during treatment. Expanded Tcells are similarly regulated in children and adults with more immunogenic cancers. This research aims to facilitate the development of precision immunotherapies for children with cancer.

The thyroid hormone activating enzyme, DIO2, is a potential pan-cancer biomarker and immunotherapy target.

Type 2 deiodinase (D2), encoded by DIO2 gene, catalyzes the activation of the prohormone thyroxine (T4) into the bioactive hormone triiodothyronine (T3) in peripheral tissues, thereby regulating the intracellular Thyroid Hormone (TH) availability. Recently, several studies have demonstrated that a drastic increase in the peripheral activation of TH, via D2, fosters tumor progression, metastasis, and immunity. To further prove the clinical relevance of D2 in human cancer, based on public Database of The Cancer Genome Atlas (TCGA), we conducted a pan-cancer analysis of DIO2 expression in various cancer types and investigated the association of DIO2 expression with the tumor microenvironment (TME) components and immune cell infiltration, along with the DIO2 genetic alteration types. Although with different expression levels between the various cancer types, the pan-cancer analysis showed that DIO2 was highly expressed in most tumors and related to the progression of some tumor types. Furthermore, DIO2 expression was also significantly correlated with TME components, immune cell infiltration, and immunoinhibitory and immunostimulatory gene subsets. The relevance of this study is that it adds a clinical relevance to the recent demonstrations that D2 accelerates tumor invasion in animal models and poses DIO2 gene as a potential prognostic marker in various human cancers.

Pan-cancer analysis shows that TNFSF4 is a potential prognostic and immunotherapeutic biomarker for multiple cancer types including liver cancer

BackgroundAs a member of the tumor necrosis factor (TNF) superfamily, tumor necrosis factor superfamily member 4 (TNFSF4) is expressed on antigen-presenting cells and activated T cells by binding to its receptor TNFRSF4. However, tumorigenicity of TNFSF4 has not been studied in pan-cancer. Therefore, comprehensive bioinformatics analysis of pan-cancer was performed to determine the mechanisms through which TNFSF4 regulates tumorigenesis.MethodsRNA-seq data for 33 cancers were analyzed from UCSC XENA database. Online websites and databases were used to investigate TNFSF4’s biological function, epigenetic modifications, genetic alterations, and tumor immunity. Furthermore, cell phenotype experiment and tumor xenotransplantation experiment were performed to determine the biological functions of TNFSF4.ResultsThe pan-cancer analysis showed that TNFSF4 was upregulated in several tumors. Significant relationships between TNFSF4 expression and single-cells data were also observed in numerous cancer types. TNFSF4 expression correlated with the expression of immune checkpoint genes and could influence various drug sensitivity. Vitro and vivo experiments showed that TNFSF4 could promote the development and progression of Hepatocellular Carcinoma (HCC).ConclusionsTNFSF4 was upregulated in multiple cancer types and promoted the development and progression of cancers through several mechanisms including regulation of the tumor-infiltration of immune cells. Our study shows that TNFSF4 is a promising prognostic and immunotherapeutic biomarker in some malignant tumors.Graphical

Matrix Metalloproteinase-9 is associated with tumor microenvironment remodeling of bladder cancer

Tumor microenvironment (TME) takes an essential part in the bladder cancer progression, which is associated with intercellular cross-talk between stroma cells and cancer. We aimed use bioinformatics tools to analyze tumor microenvironment remodeling in bladder cancer. CIBERSORT and ESTIMATE are bioinformatics tools based on deconvolution for calculating proportions of tumor-infiltrating immune cells and stromal components in TME. We utilized these two algorithms to analyze the immune components of 433 bladder cancer cases from The Cancer Genome Atlas database, aiming to compensate for the current lack of large-sample single-cell information. Then we used Cox regression to analyze the prognostic value of differentially expressed genes, and the protein–protein interaction network was constructed. Matrix Metalloproteinase-9 (MMP9) was identified as a predictive biomarker related to immune microenvironment. Using Gene Set Enrichment Analysis, the genes from the group with high MMP9 expression gathered in items related to immune diseases, and genes in the group with low MMP9 expression were negatively associated with valine, leucine and isoleucine degradation and glycosylphosphatidylinositol anchor biosynthesis. MMP9 expression and presence of macrophages M0 were positively correlated, while naïve B cells, activated dendritic cells, monocytes and plasma cells were negatively correlated. The results were confirmed by brightfield and multiplex fluorescence immunohistochemistry using stained bladder cancer and normal tissue.

Exploring prognosis and therapeutic strategies for HBV-HCC patients based on disulfidptosis-related genes.

Hepatocellular carcinoma (HCC) accounts for over 80% of primary liver cancers and is the third leading cause of cancer-related deaths worldwide. Hepatitis B virus (HBV) infection is the primary etiological factor. Disulfidptosis is a newly discovered form of regulated cell death. This study aims to develop a novel HBV-HCC prognostic signature related to disulfidptosis and explore potential therapeutic approaches through risk stratification based on disulfidptosis. Transcriptomic data from HBV-HCC patients were analyzed to identify BHDRGs. A prognostic model was established and validated using machine learning, with internal datasets and external datasets for verification. We then performed immune cell infiltration analysis, tumor microenvironment (TME) analysis, and immunotherapy-related analysis based on the prognostic signature. Besides, RT-qPCR and immunohistochemistry were conducted. A prognostic model was constructed using five genes (DLAT, STC2, POF1B, S100A9, and CPS1). A corresponding prognostic nomogram was developed based on riskScores, age, stage. Stratification by median risk score revealed a significant correlation between the prognostic signature and TME, tumor immune cell infiltration, immunotherapy efficacy, and drug sensitivity. The results of the experiments indicate that DLAT expression is higher in tumor tissues compared to adjacent tissues. DLAT expression is higher in HBV-HCC tumor tissues compared to normal tissues. This study stratifies HBV-HCC patients into distinct subgroups based on BHDRGs, establishing a prognostic model with significant implications for prognosis assessment, TME remodeling, and personalized therapy in HBV-HCC patients.

Identification of IGF2BP2 and long non-coding RNA TUG1 for the prognosis and tumour microenvironment in head and neck squamous cell carcinoma.

This study aimed to investigate the role of m6A-related long non-coding RNAs (lncRNAs) in the prognosis and tumour microenvironment of head and neck squamous cell carcinoma (HNSCC). 497 samples from The Cancer Genome Atlas were analysed to identify m6A-related lncRNAs via correlation models. Tripartite regression models, Kaplan-Meier analysis and nomograms were then utilised to assess the prognostic significance of these lncRNAs. Tumour mutation burden and immune cell infiltration analyses were also performed. Moreover, m6A-related lncRNAs expression and relation with IGF2BP2 were confirmed by RT-qPCR. The risk model revealed that high-risk scores predicted poorer survival outcomes. The area under ROC curves for predicting 1-, 3-, 5-year survival in the training set were 0.70, 0.68, and 0.64, respectively. Seven key m6A-related lncRNAs showed associations with immune checkpoint molecules, especially CTLA4 and PD-1. Finally, we found that knockdown of TUG1 repressed the expression of IGF2BP2. Our results suggest that the m6A-related lncRNA risk model has potential clinical utility in predicting prognosis and immunotherapeutic responses in patients with HNSCC. Identification of candidate compounds for immunotherapy further emphasises the model's relevance in guiding treatment decisions for HNSCC.

Tumor-infiltrating plasma cells are a prognostic factor in penile squamous cell carcinoma.

Penile cancer (PeCa) is a rare disease with poor prognosis in the metastatic stage. Neither effective adjuvant nor palliative therapeutic options are available. Research efforts in this field have so far failed to establish robust predictors of survival. To identify prognostic targets in PeCa, the current project focused on characterizing the tumor microenvironment (TME). A study cohort of 93 men with PeCa was used for the construction of a tissue microarray and immunohistochemical staining for CD3, CD4, CD8, CD20, CD56, CD138, FoxP3, and PD-L1. The quantity and spatial distribution of tumor-infiltrating immune cells were analyzed using digital image analysis. PD-L1 staining of tumor and immune cells was manually scored (combined positivity score (CPS)). T cells, T helper cells, cytotoxic T cells (CTLs), and regulatory T cells were detected in > 90% of PeCa and B cells in 88%, plasma cells in 85%, and NK cells in 23%. Approximately 50% of the PeCa samples were PD-L1 positive. In the univariate survival analysis, high PD-L1 CPS, plasma cells, CTLs, and B cells were significantly associated with favorable overall survival (OS), and the latter two with adverse recurrence-free survival. In multivariate analysis, plasma cells remained a significant factor for favorable OS (p = 0.04). In this study, the immune cells in the TME, especially plasma cells, were favorably associated with patient survival compared to other established prognostic factors in PeCa. Contemporarily, plasma cells have been discussed in the light of contributing to responses to modern immunotherapies. The results of this study support this notion.

Bioinformatics Analysis Reveals Microrchidia Family Genes as the Prognostic and Therapeutic Markers for Colorectal Cancer.

The aim of this study is to examine the role of the microrchidia (MORC) family, a group of chromatin remodeling proteins, as the therapeutic and prognostic markers for colorectal cancer (CRC). MORC protein family genes are a highly conserved nucleoprotein superfamily whose members share a common domain but have distinct biological functions. Previous studies have analyzed the roles of MORCs as epigenetic regulators and chromatin remodulators; however, the involvement of MORCs in the development and pathogenesis of CRC was less examined. The current work examined the role of the MORCs as the therapeutic and prognostic markers for CRC. The expressions and prognostic significance of MORC family genes in CRC were explored. The role of these genes in tumor immunity was comprehensively analyzed in terms of their functions in immune cell infiltration, tumor microenvironment (TME), and their interaction with immune regulatory genes such as immunosuppressive genes, immune checkpoints and immunostimulatory genes. The relations between MORC family genes, tumor mutation burden (TMB), DNA, mismatch repair (MMR), RNA methylation, microsatellite instability (MSI), and drug sensitivity were investigated using the R statistical software. The expressions of MORC4 in 150 CRC tissues and 60 paracancer tissues were detected by immunohistochemical method. CRC cell proliferation, migration, and invasion were measured by cell counting kit-8 (CCK-8), scratch assay, and transwell cell invasion assay. The expressions of MORC2 and MORC4 were significantly upregulated, whereas those of MORC1 and MORC3 were noticeably downregulated in CRC in comparison to their expressions in normal colorectal mucosal tissues. Patients with high-expressed MORC2 showed a more unfavorable prognosis than those with a low MORC2 level. Functional annotation analysis identified 100 MORC family genes with the most significant negative or positive correlations to diabetic cardiomyopathy, amyotrophic lateral sclerosis, oxidative phosphorylation, Huntington's disease, thermogenesis, Parkinson's disease, olfactory transduction, Alzheimer's disease, prion disease. MORC3 expression was positively correlated with Stromal score, Immune score and ESTIMATE score, while MORC2 expression was negatively related to the three scores in CRC, these correlations were not statistically significant. Additionally, the MORC family genes were significantly positively correlated with tumor-infiltrating immune cells such as T helper cells and exhibited close relations to some immunosuppressive genes such as CXCR4 and PVR, immunostimulatory genes such as TGFBR1, KDR, and CD160 as well as some immune checkpoint genes. It was found that the expressions of some members of MORC family genes were positively correlated with DNA methylation, MSI, TMB, MMRs, and drug sensitivity in CRC and that the mRNA and protein levels of MORC4 were remarkably upregulated in CRC tissues than in adjacent normal tissues (P<0.05). In the MORC4 knockdown group, DLD-1 cell proliferation was more inhibited than in the negative control (NC) and siRNA groups (P<0.05). Furthermore, the migratory capacity of DLD-1 cells and the number of cells crossing the basement membrane in the MORC4 knockdown group were reduced compared to the NC and siRNA groups (all P<0.05). The expressions of MORC family genes were significantly different in CRC samples, which was related to the immune cell infiltration and prognosis of CRC. Thus, the MORC family genes were considered as markers for indicating the clinical immunotherapy and prognostic outcome of CRC.

The immune-related gene CD5 is a prognostic biomarker associated with the tumor microenvironment of breast cancer.

The occurrence and progression of breast cancer (BCa) are complex processes involving multiple factors and multiple steps. The tumor microenvironment (TME) plays an important role in this process, but the functions of immune components and stromal components in the TME require further elucidation. In this study, we obtained the RNA-seq data of 1086 patients from The Cancer Genome Atlas (TCGA) database. We calculated the proportions of tumor-infiltrating immune cells (TICs) and immune and stromal components using the CIBERSORT and ESTIMATE methods, and we screened differentially expressedgenes (DEGs). Univariate Cox regression analysis of overall survival was performed on the DEGs, and a protein-protein interaction network of their protein products was generated. Finally, the hub gene CD5 was obtained. High CD5 expression was found to be associated with longer survival than low expression. Gene set enrichment analysis showed that DEGs upregulated in the high-CD5 expression group were mainly enriched in tumor- and immune-related pathways, while those upregulated in the low-expression group were enriched in protein export and lipid synthesis. TIC analysis showed that CD5 expression was positively correlated with the infiltration of CD8+ T cells, activated memory CD4+ T cells, gamma delta T cells, and M1 macrophages and negatively correlated with the infiltration of M2 macrophages. CD5 can increase anticancer immune cell infiltration and reduce M2 macrophage infiltration. These results suggest that CD5 is likely a potential prognostic biomarker and therapeutic target, providing novel insights into the treatment and prognostic assessment of BCa.