Search Results (2,287)

Eosinophils are innate immune cells that infiltrate tissues in response to cell proliferation and necrosis, which occurs during normal injury repair, parasitic infections, allergies, and cancer. Their involvement in cancer is controversial particularly with regard to tumor-associated tissue eosinophilia (TATE) and a recently defined mechanism of extracellular trap cell death (ETosis), a particular type of eosinophil cell death that is distinct from both apoptosis and necrosis. This narrative review synthesizes the literature regarding the prognostic significance of TATE, focusing on eosinophil ETosis and the important role of transmission electron microscopy (TEM) in its detection and morphological characterization. The prognostic role of TATE is contradictory: in certain tumors, it is a favorable prognostic marker, while in others, it is unfavorable. However, recent research reveals that TATE is associated with a better prognosis in non-viral neoplasms, but it may correlate with a poor prognosis in virus-related neoplasms, such as human T-lymphotropic virus type 1 (HTLV-1)-associated lymphomas and HPV-positive carcinomas. Our ultrastructural investigations revealed distinct phases of eosinophil ETosis in gastric cancer, which were defined by chromatin decondensation, plasma membrane disruption, granule discharge, and development of extracellular traps. We observed synapse-like interactions between eosinophils, exhibiting ETosis or compound exocytosis, and tumor cells, which showed various degrees of cellular damage, ultimately leading to colloid-osmotic tumor cell death. TEM provides important insights into eosinophil-mediated cytotoxicity, requiring further investigation as potential immune effector mechanisms in non-viral tumors. TATE evaluation, together with the viral status of the neoplasia, may be useful to confirm its prognostic significance and consequently its therapeutic implication in specific cancers. Full article

Tumor mutational burden (TMB) and tumor-infiltrating lymphocytes (TILs) are key biomarkers for predicting immunotherapy responses in cutaneous melanoma. The discordance between brisk TIL morphology and absent cytokine signals complicates immune profiling. We examined the interactions between TMB, TIL patterns, cytokine expression, and genomic alterations to uncover immune escape mechanisms and refine prognostic tools. A structure-based BRAF druggability analysis was performed to anchor the genomic findings in a therapeutic context. Primary cutaneous melanoma cases (N = 205) were classified as brisk (n = 65), non-brisk (n = 60), or absent TILs (n = 80) according to the American association for cancer research (AACR) guidelines. Inter-observer concordance was measured using intraclass correlation. Tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels were graded using immunohistochemistry. Eleven brisk TIL cases lacking TNF-α expression were analyzed using the (Illumina TruSight Oncology 500, Illumina-San Diego, CA, USA). Dabrafenib docking to the BRAF ATP site was performed with Glide SP/XP and rescored with Prime MM-GBSA. Brisk TILs lacking cytokine signals suggested post-translational silencing of TNF-α/IFN-γ. Among the 11 profiled cases, eight exhibited high TMB and copy number alterations, with enrichment of nine metastasis/immune regulation genes. Inter-observer concordance was high (absent TILs, 95%; brisk TILs, 90.7%). BRAF docking yielded a canonical type-I pose and strong ATP pocket engagement (ΔG_bind −84.93 kcal·mol⁻¹). Single biomarkers are insufficient for diagnosis. A multiparametric framework combining histology, cytokine immunohistochemistry (IHC), and genomic profiling enhances stratification and reveals immune escape pathways, with BRAF modeling providing a mechanistic anchor for the targeted therapy. Full article

Peritoneal carcinomatosis (PC) and malignant pleural effusions (MPE) are two common complications of cancers metastatic to the respective body cavities. A PC diagnosis indicates metastasis to the tissue lining the abdominal cavity and is most common in patients with gastrointestinal and gynecological cancers. It is often accompanied by ascites, an accumulation of serous fluid in the abdomen. MPE presents as the accumulation of fluid in the space between the lungs and chest wall. It is a common terminal event in patients diagnosed with breast cancer, lung cancer, lymphoma, and mesothelial cancers, and less commonly, in a wide variety of other epithelial cancers. Due to the aggressive nature of cavitary tumors, the outcome of current treatments for both PC and MPE remains bleak. Although PC and MPE are characteristically affected by different sets of primary tumors (lung/breast/mesothelioma for MPE and gynecologic/gastrointestinal for PC), their environments share common cytokines and cellular components. Owing to the unique cytokine and chemokine content, this environment promotes aggressive tumor behavior and paradoxically both recruits and suppresses central memory and effector memory T cells. The cellular and secretomic complexity of the cavitary tumor environment renders most currently available therapeutics ineffective but also invites approaches that leverage the robust T-cell infiltrate while addressing the causes of local suppression of anti-tumor immunity. Interactions between the heterogeneous components of the tumor environment are an area of active research. We highlight the roles of the immune cell infiltrate, stromal cells, and tumor cells, and the soluble products that they secrete into their environment. A more comprehensive understanding of the cavitary tumor environment can be expected to lead to better immunotherapeutic approaches to these devastating conditions. Full article

Introduction: The analysis of exhaustion marker expression, like immune checkpoint molecules (ICMs) on tumor-infiltrating lymphocytes as well as peripheral immune cells of patients with head and neck squamous cell carcinoma (HNSCC), is of high interest since it reveals information about the patient’s immune status and the effectiveness of immune modulation. However, data regarding age-dependent expression are lacking. Here, we demonstrate an increase in most ICMs associated with age and disease, suggesting immune checkpoint modulation as an evidence-based option for the treatment of aged HNSCC patients. Material and Methods: Peripheral blood mononuclear cells (PBMCs) (healthy: n = 30 with an age range from 21 to 84 years/HNSCC: n = 37 with an age range from 37 to 94 years) were analyzed via flow cytometry following (density gradient separation) standard protocol. Flow cytometry was performed using CD4 and CD8 as backbone markers as well as co-stimulatory molecules like CD137, OX40, GITR, and CD27 or ICM like PD-1, CTLA4, BTLA, LAG3, or TIM3 using a Gallios flow cytometer (Beckman Coulter, Brea, CA, USA). Results: We found a statistically significant decreased ICM expression on the PBMCs of healthy donors with increasing age. However, the expression of ICMs in HNSCC was significantly increased (PD1 on CD4⁺ T cells: p = 0.001), while we found a decreased co-stimulatory molecule expression (e.g., CD27 on CD4⁺ T cells and CD39⁺ T cells: p = 0.003 and p = 0.009, respectively). Immune cells of HPV^neg HNSCC have a significant age-dependent decrease in CD27 expression on CD8⁺, CD4⁺, and CD39⁺ T cells (p = 0.0426, p = 0.0078, and p = 0.0078, respectively). Conclusions: This study sheds light on the changing co-stimulatory molecule/ICM expression regarding the patient’s age and reveals an increase in most immune checkpoint molecules for HNSCC patients according to their age. This new evidence is valuable in ensuring individualized therapeutic approaches in the increasingly relevant field of checkpoint inhibition, even in old age. Full article

Immunogenic cell death (ICD) is a specialized form of cell death that triggers antitumor immune responses. In tumors, ICD promotes the release of tumor-associated and tumor-specific antigens, thereby reshaping the immune microenvironment, restoring antitumor immunity, and facilitating tumor eradication. However, the regulatory mechanisms of ICD and its immunological effects vary across tumor types, and a comprehensive understanding remains limited. We systematically analyzed the expression of 34 ICD-related regulatory genes across 33 tumor types. Differential expression at the RNA, copy number variation (CNV), and DNA methylation levels was assessed in relation to clinical features. Associations between patient survival and RNA expression, CNVs, single-nucleotide variations (SNVs), and methylation were evaluated. Patients were stratified into immunological subtypes and further divided into high- and low-risk groups based on optimal prognostic models built using a machine learning framework. We explored the relationships between ICD-related genes and immune cell infiltration, stemness, heterogeneity, immune scores, immune checkpoint and regulatory genes, and subtype-specific expression patterns. Moreover, we examined the influence of immunotherapy and anticancer immune responses, applied three machine learning algorithms to identify prognostic biomarkers, and performed drug prediction and molecular docking analyses to nominate therapeutic targets. ICD-related genes were predominantly overexpressed in ESCA, GBM, KIRC, LGG, PAAD, and STAD. RNA expression of most ICD-related genes was associated with poor prognosis, while DNA methylation of these genes showed significant survival correlations in LGG and UVM. Prognostic models were successfully established for 18 cancer types, revealing intrinsic immune regulatory mechanisms of ICD-related genes. Machine learning identified several key prognostic biomarkers across cancers, among which NT5E emerged as a predictive biomarker in head and neck squamous cell carcinoma (HNSC), mediating tumor–immune interactions through multiple ligand–receptor pairs. This study provides a comprehensive view of ICD-related genes across cancers, identifies NT5E as a potential biomarker in HNSC, and highlights novel targets for predicting immunotherapy response and improving clinical outcomes in cancer patients. Full article

The progression of pancreatic cancer (PC) is significantly influenced by the immune system. In the United States, PC is the third leading cause of cancer-related mortality. The high lethality of PC is attributed to its immunological advantage, which is facilitated by an immunosuppressive microenvironment, a low mutational burden, and minimal T-cell infiltration. Although immunotherapies, such as checkpoint blockades or genetically engineered T cells, have not yet demonstrated viability, there is a growing body of evidence suggesting that innovative combinations of conventional therapies and various procedures may lead to effective immunotherapy in the treatment of PC. This review focuses on the importance of the tumor microenvironment and the promising role of immunotherapies in PC. Full article

Endometriosis is a chronic, estrogen-dependent inflammatory disease with heterogeneous clinical manifestations and uncertain systemic immune involvement. This study aimed to characterize peripheral immune profiles and circulating tumor markers in women with ovarian endometrioma (OE) and deep infiltrating endometriosis (DIE), and to explore their associations with disease severity, symptom burden, and physical health perception. Peripheral blood leukocyte subsets, plasma cytokines, and tumor markers (CA125, CA19-9, CEA, HE4) were analyzed in 146 patients and 50 healthy controls. OE was associated with increased monocyte counts and reduced neutrophil proportions, while DIE showed elevated levels of IL-8 and Galectin-1. IL-33 levels correlated negatively with the revised American Society for Reproductive Medicine (rASRM) scores and positively with neutrophil proportion, suggesting a role in systemic immune regulation. Tumor marker levels varied by subtype: CA19-9 was higher in OE, and CEA in DIE. CA125 correlated with disease severity, and CEA with monocyte levels. Exploratory heatmaps revealed consistent immune-tumor associations linked to anatomical severity and symptom profiles. Although exploratory, these findings highlight the presence of distinct systemic immune patterns in endometriosis and support the potential of integrative blood-based biomarkers for future diagnostic and stratification strategies. Full article

Background: Colorectal cancer (CRC) represents a major global health challenge, characterized by rising incidence and mortality rates, necessitating improved diagnostic and therapeutic approaches. This study aimed to elucidate the expression and functional role of PAK6, a protein linked to cancer progression, as a potential biomarker for CRC. Methods: Utilizing comprehensive analyses of transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we performed differential expression assessments, survival analyses, and functional enrichment studies. Results: Our findings demonstrate a significant upregulation of PAK6 in CRC tissues compared to adjacent normal tissues (p < 0.001), with a diagnostic AUC of 0.855, indicating its potential utility as a reliable biomarker for early detection. High PAK6 expression was significantly associated with aggressive clinicopathological features, including poor differentiation, residual tumor presence and reduced overall survival (HR = 1.72, p = 0.004). Functional enrichment analyses revealed PAK6’s involvement in critical biological processes such as cell cycle regulation, alongside its correlation with immune infiltration, particularly NK and CD8⁺ T cells. Moreover, PAK6 expression positively correlated with chemokines involved in immune cell recruitment, suggesting its role in modulating the tumor immune microenvironment. Conclusions: Our study underscores the significance of PAK6 as a diagnostic and prognostic biomarker in CRC, with the potential to inform targeted therapeutic strategies and enhance patient outcomes. Future research should focus on validating these findings in larger cohorts and exploring PAK6-targeted interventions to improve immunotherapeutic responses in CRC patients Full article

Background: Personalized cancer vaccines (PCVs) are a promising form of cancer immunotherapy, capable of eliciting robust neoantigen-specific immune responses. However, cancer neoantigens are variable in terms of immunogenicity, and PCVs may be less effective when targeting weak neoantigens. Strong and durable immune responses are also likely to be critical for vaccine efficacy. Interleukin-7 (IL-7) is a common gamma-chain cytokine known to support T cell development and survival, and a long-acting form of recombinant human IL-7 fused with hybrid Fc (rhIL-7-hyFc) has shown potential to enhance immune responses in early-stage clinical trials. Methods: In this study, we evaluated the ability of rhIL-7-hyFc to serve as a molecular adjuvant to a DNA PCV in the E0771 murine breast cancer model. Results: We found that the combination of rhIL-7-hyFc and DNA PCV treatment prolonged neoantigen-specific CD8+ T cell responses, improved functional memory as measured based on in vivo cytotoxicity, and increased the number of neoantigen-specific tumor-infiltrating lymphocytes (TILs), resulting in improved prophylactic tumor protection and durable memory responses. Conclusions: Our findings support the potential of rhIL-7-hyFc to enhance the efficacy of PCVs and suggest clinical utility for adjuvant rhIL-7-hyFc in cancer immunotherapy. Full article

The highly heterogeneous and invasive nature characteristic of high-grade gliomas (HGG) has historically limited the efficacy of standard-of-care approaches, resulting in poor prognosis and treatment outcomes. Novel immunotherapies have shown remarkable potential to promote antitumoral immune responses and allow for long-term tumor remission. However, the complexity of the HGG tumor microenvironment and the dynamic immunological changes associated with immunotherapy response can limit the diagnostic utility of conventional magnetic resonance imaging (MRI) and positron emission tomography (PET) approaches. Consequently, distinguishing true tumor progression from immunotherapy-related effects often requires prolonged clinical follow-up over several months. To address this, novel quantitative MRI and PET-based approaches are being evaluated in preclinical studies and clinical trials. These advanced imaging methods target key biological features of the tumor microenvironment, including vascularity, cellularity, intratumoral habitats, tracer pharmacokinetics and immune infiltration, and can provide metrics to stratify patient response at earlier timepoints to support clinical decision making and improve treatment outcomes. This review highlights key HGG biological characteristics, describes standard-of-care and emerging therapeutic strategies, and discusses both conventional and advanced imaging methods to characterize immunotherapeutic responses. Full article

Regulatory T cells (Tregs) are a specialized subset of CD4+ T lymphocytes essential for maintaining immune tolerance and preventing autoimmunity. However, in breast cancer, tumors exploit Tregs to establish an immunosuppressive microenvironment that enables immune evasion, accelerates progression, and contributes to therapeutic resistance. This review synthesizes current evidence on the role of Tregs in invasive breast cancer (IBC), highlighting their prognostic significance across molecular subtypes, mechanisms of immune suppression, and impact on treatment response. We integrated mechanistic and clinical insights to discuss opportunities for Treg-targeted therapeutic strategies, with attention paid to challenges such as autoimmunity, compensatory resistance, and subtype-specific heterogeneity. Finally, we outline future directions, including biomarker-driven precision medicine, novel therapeutic combinations, advanced preclinical models, as well as potential artificial intelligence-assisted approaches that aim to selectively disrupt tumor-promoting Treg functions while preserving the systemic immune balance. Full article

Pre-clinical animal studies evaluating the ‘flash effect’ caused by ultra-high dose rate (≥40 Gy/s) favorably spares normal tissue from radiation-caused toxicity while maintaining anti-tumor effects like conventional (CONV) radiation. The goal of this study is to leverage an immune response resulting from the treatment combination of flash radiotherapy (Flash-RT) and LIFE (liquid immunogenic fiducial eluter) biomaterial incorporating an anti-mouse CD40 monoclonal antibody to enhance the therapeutic ratio in pancreatic cancer. Methods: A small animal FLASH radiation research platform (FLASH-SARRP) was utilized to deliver both ultra-high and CONV dose-rate irradiation to treat syngeneic subcutaneous pancreatic tumors generated in 8–10-week-old male and female C57BL6 mice. The efficacy of FLASH versus CONV radiotherapy (RT) at varying doses of 5, 8, 10, and 15 Gy delivered in a single fraction was evaluated by assessing tumor growth and mice survival over time or comparing tumor weight at 10 days post-treatment. Results: Similar tumor control capability was observed by the high-dose rate and conventional RT related to the control group. Nevertheless, longer survival was observed for the FLASH group at 5 Gy compared to CONV and control at either 5 Gy, 10 Gy, or 15 Gy doses. Multiplex immunofluorescence and immunohistochemistry results showed higher T-cell infiltration within the combination of RT (either FLASH or CONV) and LIFE biomaterial-treated tumors compared to the control cohort. Conclusions: This animal study serves as an impetus for future studies leveraging the immune response using the combination of FLASH and LIFE Biomaterial to enhance the efficacy of pancreatic cancer treatment. Full article

Background/Objectives: Cutaneous angiosarcoma (CAS) is a rare and aggressive endothelial malignancy with a high rate of local recurrence and distant metastasis. In advanced cases, where surgical resection is not feasible, systemic therapy remains the cornerstone of treatment. This review aims to summarize the current landscape of systemic therapies for unresectable or metastatic CAS and discuss emerging strategies, particularly focusing on immune checkpoint inhibitors (ICIs). Methods: A comprehensive review of the literature was conducted, including clinical trials, retrospective studies, and case series focusing on systemic treatments for advanced CAS. Therapeutic approaches covered include cytotoxic chemotherapy, molecular targeted therapies, and ICIs, as well as combination strategies. Special attention was given to biomarker studies and ongoing clinical trials. Results: Taxane-based chemotherapy, particularly paclitaxel, has demonstrated clinical activity and remains a standard option. Molecular targeted agents such as pazopanib have yielded modest efficacy. Recent trials of ICIs, including the SWOG S1609 DART and AngioCheck studies, have shown encouraging results in select subgroups, especially tumors from sun-exposed regions associated with high tumor mutational burden (TMB). Although AngioCheck did not meet its predefined response criteria, a subset of patients achieved disease control. Biomarkers such as TMB, PD-L1 expression, and tumor-infiltrating lymphocytes are under investigation to guide patient selection. Combination therapies with ICIs and tyrosine kinase inhibitors (TKIs) are being actively explored. Conclusions: While systemic therapies for CAS remain limited in efficacy, ICIs—particularly in combination with TKIs—represent a promising avenue. Future trials should emphasize biomarker-driven, CAS-specific strategies to improve clinical outcomes in this challenging malignancy. Full article

Novel research data in different cancer types indicate that mutations within PIK3CA might serve as a biomarker of an improved response to immune therapy. Therefore, the aim of this study was to evaluate and examine possible differences in the tumor microenvironment composition and PD-L1 expression as well the prognostic significance of CD4, CD8, CD68, and CD163 in PIK3CA mutated and non-mutated hormone receptor positive and HER2 negative (HR+/HER2−) breast carcinoma. Breast carcinoma tissue was analyzed by Cobas PIK3CA mutation test for the presence of PIK3CA mutation and immunohistochemistry was applied to assess PD-L1 expression and CD4, CD8, CD68, and CD163 infiltration within tumor. Statistically significant association was observed between PD-L1 expression and the presence of PIK3CA exon 20 mutation (p = 0.044), with PD-L1–positive patients predominantly harboring this mutation. Tumors harboring PIK3CA mutations exhibited moderate to strong statistically significant positive correlations between PD-L1 expression and infiltration by CD8 cells (rs = 0.462, p = 0.0027), CD68 cells (rs = 0.398, p = 0.0134), and CD163 cells (rs = 0.617, p < 0.0001). In patients with PIK3CA mutation and exon 20 PIK3CA mutation there was statistically significant longer survival without recurrence (p = 0.026 and p = 0.041, respectively). Research regarding PD-L1 expression, immune cells and PIK3CA mutations might have an impact on how to determine therapeutic approaches for patients with HR+/HER2− breast carcinoma. Full article

Background: Breast cancer remains a predominant malignancy among females globally, and the tumor microenvironment (TME) exerts a pivotal role in its progression. Despite notable advancements in diagnostic and therapeutic modalities, resistance to conventional therapies persists as a critical hurdle, underscoring the necessity of exploring TME-related prognostic biomarkers. Methods: To elucidate the role of the TME in breast cancer progression and identify potential prognostic biomarkers, we analyzed RNA-seq data from 1081 breast cancer cases and 99 normal controls to assess tumor-infiltrating immune cells (TICs) and stromal components. Differential gene expression analysis identified genes correlated with ImmuneScore and StromalScore. A protein–protein interaction (PPI) network was constructed, followed by univariate Cox regression to pinpoint survival-associated genes. JCHAIN, significantly linked to survival outcomes, was selected for further investigation. Gene Set Enrichment Analysis (GSEA) and TIC correlation analyses were performed to explore its associations with immune pathways. Additionally, immunohistochemistry (IHC) and multiplexed immunofluorescence (mIF) were performed on 61 clinical samples. Results: High ImmuneScore was associated with improved survival. Joining chain of multimeric IgA and IgM (JCHAIN) expression was notably reduced in tumor tissues, with low expression correlating with poorer prognosis. GSEA highlighted immune-related pathways enriched in high JCHAIN expression groups. TIC analysis revealed positive correlations with CD8+ T cells and M1 macrophages. IHC and mIF validations further confirmed decreased JCHAIN protein expression in tumor tissues, and higher JCHAIN expression was associated with increased M1 macrophage density. Conclusions: JCHAIN serves as a promising prognostic biomarker in breast cancer, reflecting immune activity within the TME, providing valuable insights into immune-stromal interactions and the therapeutic potential of JCHAIN. Full article