Search Results (490)

Background/Objectives: This study aimed to evaluate the prognostic value of ¹⁸F-FDG PET/CT-based secondary lymphoid organ metabolic ratios—spleen/liver (SLR), bone marrow/liver (BLR), and ileocecal region/liver (ILR)—and hematological inflammation markers (neutrophil/lymphocyte ratio [NLR] and systemic immune-inflammation index [SII]) obtained before nivolumab treatment in relation to survival in patients with advanced non-small cell lung cancer (NSCLC). Methods: This retrospective single-center study included 79 advanced NSCLC patients who were treated with nivolumab monotherapy at Marmara University Faculty of Medicine Hospital between 2022 and 2024. Pretreatment SLR, BLR, and ILR ratios were calculated from ¹⁸F-FDG PET/CT examinations; NLR and SII values were obtained from hematological data. Survival outcomes were analyzed using the Kaplan–Meier method, and prognostic factors were assessed using Cox proportional hazards regression analysis. In a subset of patients, an exploratory longitudinal analysis was performed using early follow-up PET/CT to assess follow-up-to-baseline changes in immune-organ metabolic ratios in relation to overall survival. Results: High NLR and SII levels were significantly associated with shorter progression-free survival and overall survival. In contrast, no significant associations were observed between PET/CT-derived metabolic ratios (SLR, BLR, and ILR) and survival. Multivariate analysis identified the presence of liver metastases and a high NLR as independent adverse prognostic factors for overall survival. Conclusions: In this homogeneous real-world cohort treated exclusively with single-agent nivolumab, PET/CT-derived secondary lymphoid organ metabolic ratios showed limited prognostic value at baseline and during early on-treatment assessment. In contrast, hematological inflammation markers, especially high NLR levels, are strong prognostic indicators of survival and may complement established clinical factors in risk stratification. Full article

Background/Objectives: Penile squamous cell carcinoma (PSCC) is a rare malignancy with poor prognosis in advanced and recurrent disease, and therapeutic options remain limited. Increasing evidence suggests that the tumor immune microenvironment (TIME), including immune cell composition and spatial organization, plays a critical role in tumor progression and survival outcomes. This study aimed to characterize immune cell density and geospatial clustering patterns within the TIME of PSCC and to evaluate their associations with clinical outcomes. Methods: Multiplex immunofluorescence (mIF) was performed on tumor samples from 57 patients with PSCC using a panel of immune markers to identify lymphoid and myeloid cell populations. Immune cell densities were quantified within tumoral and stromal compartments. Spatial relationships among immune cells and between immune cells and tumor cells were analyzed using point pattern analysis. Survival outcomes, including overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS), were assessed using Kaplan–Meier methods and Cox proportional hazards models, with analyses stratified by nodal and human papillomavirus (HPV) status. Results: Higher intratumoral and stromal densities of pro-immunogenic M1 macrophages were associated with improved OS. Increased densities of CD3⁺CD4⁺ helper T cells in both compartments were also associated with favorable survival outcomes. In contrast, close clustering of pro-tumorigenic M2 macrophages with tumor cells and with one another was associated with worse OS, RFS, and CSS. Bivariate clustering of helper T cells with tumor cells was associated with improved OS, including among patients with node-positive disease. Survival outcomes did not differ significantly by HPV status in patients with high helper T cell clustering. Conclusions: Immune cell density and spatial organization within the TIME are associated with survival outcomes in PSCC. Favorable patterns involving helper T cells and M1 macrophages correlate with improved survival, whereas clustering of M2 macrophages is associated with poorer outcomes, supporting the relevance of spatial immune profiling in this disease. Full article

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, mainly due to its high recurrence rate after curative treatments. The macrotrabecular-massive (MTM) subtype has recently been recognized as an aggressive histologic variant associated with vascular invasion and poor differentiation. This study aimed to investigate the prognostic impact of the MTM subtype on recurrence after surgical resection of HCC. Methods: We retrospectively reviewed 171 patients who underwent curative hepatic resection for HCC between January 2007 and December 2017 at Gangnam Severance Hospital, Seoul, Korea. Clinicopathologic parameters, including immune-related features such as lymphoid infiltration and tertiary lymphoid structures (TLSs), were evaluated. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression analyses. Results: During a median follow-up of 4.4 ± 3.4 years, 74 patients (43.3%) experienced recurrence. The MTM subtype was significantly more frequent in the recurrence group than in the non-recurrence group (47.3% vs. 21.6%, p < 0.001). Multivariate analysis identified MTM subtype as an independent predictor of recurrence (hazard ratio, 1.88; 95% CI, 1.14–3.10; p = 0.013). Lymphoid infiltration and TLSs were not associated with prognosis. Kaplan–Meier analysis showed higher recurrence in MTM-positive cases (p = 0.001), whereas OS did not differ significantly (p = 0.094). Conclusions: The macrotrabecular-massive subtype is an independent histopathologic predictor of recurrence after curative resection in HCC. Incorporating MTM subtype recognition into postoperative risk assessment may enhance patient stratification and inform future adjuvant therapy strategies. Full article

Background/objectives: Understanding the immune landscape in cervical cancer is critical to the development of improved therapeutics. This study investigated the immune microenvironment in early-stage cervical cancer with a focus on B and T cell immune aggregates, i.e., lymphoid aggregates (LAs) and tertiary lymphoid structures (TLSs). Methods: Using multispectral imaging, we interrogated a cohort of patients with clinical stage I squamous or adenocarcinoma of the cervix with a focus on T and B cell spatial location and organization. Despite early-stage disease, recurrence was common at 37%, highlighting the need to identify patients at high risk for recurrence. Results: We demonstrated that high CD8+ T cell infiltration correlated significantly with improved overall survival (OS), particularly in patients with adenocarcinoma histology. CD8+ T cells colocalized with B cells, suggesting the formation of a more sophisticated cellular neighborhood, i.e., TLS, which has prognostic benefit in other solid tumors. CXCL13, a chemokine associated with TLS formation, correlated with improved recurrence-free survival. The combination of high CXCL13 and lymphoid structures correlated with improved OS. However, most immune structures in cervical cancer were lymphoid aggregates (LAs) that lack features of more developed TLS, such as high endothelial venules (HEVs) and germinal centers (GCs), highlighting a lack of full immune activation in this microenvironment. Validation in The Cancer Genome Atlas (TCGA) cohort illustrated similar trends in survival. Conclusions: Collectively, this work demonstrates the prognostic significance of immune infiltration and eventual TLS induction in early cervical cancer and presents potential future therapeutic targets. Full article

Background: Electrochemotherapy (ECT) is a clinically validated local ablative treatment increasingly recognized for its ability to induce immunogenic cell death and stimulate antitumor immunity. Its combination with immune checkpoint inhibitors, such as anti-PD-1 antibodies, may enhance systemic immune responses and improve therapeutic efficacy, particularly in poorly immunogenic tumors. Methods: We evaluated the antitumor effectiveness of ECT combined with a murine analog of the anti-PD-1 antibody in four syngeneic murine tumor models with differing histology and immune status: WEHI fibrosarcoma, CT26 and MC38 colorectal carcinoma, and 4T1 mammary carcinoma. In vitro cytotoxicity assays assessed tumor cell sensitivity to ECT, while in vivo experiments evaluated complete response (CR) rates, immune cell infiltration, and long-term immune memory through secondary tumor challenge. Immunohistochemical analysis of CD4⁺, CD8⁺, and granzyme B⁺ effector cells. Results: In vitro, WEHI cells exhibited the highest sensitivity to ECT. In vivo, ECT monotherapy induced CRs in 100% of WEHI tumors, 60% of CT26, 17% of 4T1, and 15% of MC38. The addition of anti-PD-1 significantly enhanced outcomes in less responsive models, increasing CRs to 90% in CT26, 91% in MC38, and 53% in 4T1. Combination therapy promoted pronounced infiltration of CD4⁺, CD8⁺, and granzyme B⁺ T cells and the formation of tertiary lymphoid structure, particularly in MC38 tumors. Secondary challenge experiments confirmed long-term immune memory in CT26 and MC38 models and induced memory in 4T1, which was absent following monotherapy. Conclusions: ECT synergizes with PD-1 blockade to potentiate local and systemic antitumor immunity, overcoming immune resistance in poorly immunogenic tumors. These findings support further clinical development of ECT in combination with immune checkpoint inhibitors as a component of personalized cancer immunotherapy. Full article

The thymus, as the primary lymphoid organ for T cell development, orchestrates a complex continuum of processes encompassing precursor migration, lymphocyte lineage commitment, and antigen-guided selection to generate a self-tolerant and immunocompetent T cell repertoire. The thymus is anatomically divided into the cortex, which facilitates the positive selection of thymocytes through interactions between T cell receptors and self-peptide–MHC complexes on cortical epithelial cells, and the medulla, which mediates negative selection by medullary epithelial cells in concert with dendritic cells via the presentation of self-antigens. Key regulatory elements controlling thymocyte development include the transcription factors ThPOK/Runx3 and Sox13/PLZF, chemokine-driven migration mediated by CXCR4 and CCR7, and cytokine signaling. These components collectively exert a profound influence on the final outcome: the establishment of TCR affinity thresholds for tissue-specific antigens in mature T cells. In summary, the integration of multidimensional methodologies highlights the pivotal role of the thymus in immune tolerance, with translational implications for autoimmunity, cancer immunotherapy, and regenerative medicine, as reviewed herein. Full article

Tertiary lymphoid structures (TLS) arise from lymphoid neogenesis in non-lymphoid organs and are driven by persistent inflammation mediated by chemokines and cytokines. In cancer, TLS orchestrate immune mechanisms relevant to tumor growth and thereby influence clinical outcomes. Observations of a correlation between the presence of TLS and clinical benefits in cancer patients, which suggests that TLS may serve as prognostic and predictive biomarkers, have prompted increased investigation of TLS in tumors. Accumulating evidence indicates that the prognostic and predictive value of TLS is context-dependent and relevant to their cellular composition and functional state. Combining assessments of tumor-infiltrating lymphocytes (TILs) with TLS features yields a more refined prognostic tool by capturing both local immune activity and aspects of the broader tumor immune microenvironment. Improved understanding of TLS biology and of their interactions with TILs can enhance predictions of therapeutic response. Furthermore, therapeutic modulation of TLS composition or function to favor antitumor immunity represents a promising strategy to improve treatment outcomes. Full article

Hematological malignancies such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphomas, and multiple myeloma remain difficult to model ex vivo because conventional two-dimensional (2D) cultures and murine systems fail to reproduce the spatial, metabolic, vascular, and immune complexity of human bone marrow and lymphoid niches. Recent advances in three-dimensional (3D) platforms—including spheroids, engineered organoid-like marrow models, and microfluidic niche-on-a-chip systems—now allow for a more physiological replication of stromal, endothelial, and immune interactions that drive resistance and relapse. In this review, we introduce explicit definitions distinguishing spheroids, organoid-like constructs, true hematopoietic organoids, and microfluidic devices to establish a unified framework for hematologic 3D modeling. We synthesize applications across AML, CML, lymphoma, and myeloma, highlighting mechanistic insights, strengths, and limitations unique to each disease. Finally, we outline a translational roadmap that integrates bioprinting, perfusable vasculature, immune reconstitution, and AI-driven analytics toward next-generation patient-specific platforms. These innovations position 3D marrow-mimetic systems as essential tools for precision oncology in blood cancers. Full article

Fibroblast activation protein (FAP), a transmembrane serine protease expressed primarily in pathological conditions, plays a pivotal role in tumor progression. Despite extensive studies on FAP in solid tumors, its role in hematologic cancers, particularly lymphoid malignancies, remains underexplored. This study aimed to investigate the level and activity of soluble FAP (sFAP) in pre-therapeutic serum samples from 120 lymphoma patients. We measured sFAP serum levels using time-resolved immunofluorometric assay and sFAP activity with Förster resonance energy transfer assay. In addition, immunohistochemistry was used to analyze intratumoral FAP expression in tissue biopsies from a subset of B-cell lymphoma patients (n = 34). Notably, the results revealed significantly reduced circulating sFAP levels (p = 0.002) and activity (p < 0.001) in aggressive disease subtypes compared with indolent subtypes and healthy individuals. At the time of diagnosis, low sFAP activity correlated with inferior overall survival (both p < 0.001) in patients with the aggressive entities, suggesting altered FAP functionality in these tumors. Interestingly, measuring intratumoral FAP levels revealed an inverse pattern, with diffuse large B-cell lymphoma showing higher tissue FAP localization compared with follicular lymphoma (p < 0.001). These findings provide new insights into the biological and clinical significance of FAP in lymphoid malignancies, particularly highlighting the importance of sFAP activity as a potential prognostic marker in aggressive lymphoid malignancies. Full article

The immune control of cancer growth is an area of active investigation. In this study, we demonstrated the feasibility of using standard immunohistochemistry methods in conjunction with a set of newly developed chromogens to demonstrate immune cell markers in a multiplex staining system. Immune infiltrating cells in breast cancer were identified using antibodies to CD20 (B-cells), CD3 (T-cells), and CD163 (macrophages). Additionally, the tumor compartment was identified using cytokeratin (AE1/AE3), and Ki67 was used to determine the proliferation index. These stains showed a significant immune cell infiltrate surrounding and within the tumors. B-cells, T-cells, and macrophages were abundant at the tumor periphery, particularly in areas where tertiary lymphoid structures were also present. In contrast, B-cells were significantly reduced within the tumor interior compared to an abundant infiltrate of T-cells and macrophages. Patterns of B-cell, T-cell, and macrophage infiltration were identified. Depending upon the particular set of markers chosen for analysis, a simple visual examination, without the aid of computer-assisted imaging systems, was sufficient to differentiate up to five different markers. Full article

The lymphatic system is essential for maintaining the body’s fluid balance, lipid absorption, and immune regulation. The dysfunction of the lymphatic system is associated with a wide spectrum of disorders. These disorders include primary and secondary lymphedema, congenital malformations, and lymphatic neoplasms. In cancer patients, lymphatic remodeling is essential, which facilitates tumor progression and metastasis, while tertiary lymphoid structures (TLSs) develop during chronic inflammation and may be involved in anti-tumor immunity. This review highlights the immunological basis of lymphatic disorders, with a particular focus on cellular and molecular biomarkers that define disease states. The recent advances in molecular imaging techniques, such as ultrasonography (US), computed tomography (CT), and magnetic resonance lymphography (MRL), have improved and identified the diagnosis and therapeutic targets for lymphedema. Moreover, nanobiotechnology and nano-delivery tools have further enhanced the visibility of cancer cells by imaging. Artificial Intelligence (AI) in lymphatic systems have offered a new spectrum for disease prediction using forms of AI such as natural language processing (NLP), machine learning (ML), robotics-assisted approaches, fussy model (FM), and natural language processing (NLP)-based algorithms. Collectively, these advanced tools have improved diagnostic approaches and reveal exciting opportunities for future research and new therapeutic developments in patient care. Full article

Non-muscle invasive bladder cancer (NMIBC) accounts for the majority of bladder cancer diagnoses and remains a clinical challenge due to its high recurrence and progression rates despite intravesical Bacillus Calmette–Guérin (BCG) therapy. In recent years, tumor-infiltrating lymphocytes (TILs) have emerged as promising biomarkers, reflecting the interplay between the tumor and host immune system. However, the evidence regarding their prognostic and predictive role is still conflicting, largely due to methodological heterogeneity, lack of standardized evaluation criteria, and limited prospective validation. This narrative review summarizes the current knowledge on TILs in NMIBC, focusing on their compartmental distribution (stromal, intraepithelial, and tumor–stroma interface), compositional diversity (CD4⁺, CD8⁺, Treg, B cells), and spatial dynamics. Special attention is given to their role in predicting response to BCG immunotherapy, the contribution of tumor-associated macrophages and tertiary lymphoid structures, and the emergence of immune escape pathways, including Programmed Death-Ligand 1 (PD-L1) and the HLA-E/NKG2A axis. Advances in digital pathology, spatial transcriptomics, and integrated immunoscore models provide more accurate metrics compared to simple cell counts, highlighting the importance of functional and spatial signatures. Despite encouraging progress, TILs are not yet ready for routine incorporation into histopathological reporting. Future directions include standardized assessment, integration with molecular biomarkers, and prospective multicenter validation to enable their translation into risk stratification and personalized therapeutic decision-making. Full article

In response to growing clinical demands for more targeted and effective immunotherapies to treat cancer, biomaterial-based strategies have emerged as powerful tools for locally regulating immune responses. Among these, hydrogels, a class of biocompatible and tunable polymeric networks, are increasingly being leveraged for their high versatility and adaptability for creating tailored immune environments. By enabling controlled delivery of immune cues and direct cellular engineering, hydrogels utilized in vivo can precisely regulate both innate and adaptive immune responses while minimizing systemic toxicity. In this review, we outline essential hydrogel design features necessary for in vivo functionality including injectability, degradation kinetics, and immune-specific functionalization. Building on these principles, we explore how hydrogels have been employed to enhance T cell activation and dendritic cell maturation and guide macrophage reprogramming. Beyond cellular modulation, we further examine the use of hydrogels for cytokine and immunoregulatory agent delivery, tumor microenvironment remodeling, and the creation of tertiary-like lymphoid structures. Finally, we review recently completed and ongoing clinical trials of hydrogels in the cancer immunotherapy space. Together, these insights underscore the growing potential of in vivo hydrogel systems as immuno-interactive platforms capable of reshaping immune responses across diverse disease contexts. Full article

Cancer immunotherapy has redefined oncology’s goals, aiming for durable systemic immunity rather than mere cytoreduction. However, many solid tumors remain refractory due to immunosuppressive microenvironments and antigenic heterogeneity. Local tumor ablation techniques—including radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, irreversible electroporation (IRE), and high-intensity focused ultrasound (HIFU)—are being re-evaluated beyond their historic cytoreductive role. This comprehensive review synthesizes the paradigm of tumor ablation as an in situ vaccination strategy, a concept that leverages the tumor itself as a source of antigens and the ablation process to generate endogenous adjuvants. We detail the mechanistic underpinnings, highlighting how ablation induces immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) such as calreticulin, ATP, HMGB1, and cytosolic DNA. These signals activate innate immunity via pathways like cGAS-STING, promote dendritic cell maturation, and facilitate epitope spreading. We critically examine the determinants of efficacy, including the critical impact of ablation modality on the “DAMP signature,” the necessity of complete ablation, and the pivotal role of the host’s immune contexture. Furthermore, we explore the induction of tertiary lymphoid structures (TLS) as a key anatomical site for sustained immune priming. Translational strategies are extensively discussed, focusing on optimizing procedural techniques, rationally combining ablation with immune checkpoint inhibitors (ICIs) and innate immune agonists, and developing a robust biomarker framework. By adopting the core principles of vaccinology—meticulous attention to antigen, adjuvant, route, and schedule—ablation can be engineered into a reproducible platform for systemic immunotherapy. This review concludes by addressing current limitations and outlining a roadmap for clinical translation, positioning interventional oncology as a central discipline in the future of immuno-oncology. Full article

Background: Esophageal cancer remains a highly aggressive malignant tumor with poor prognosis, despite advances in combination therapies and novel immunotherapies. Tertiary lymphoid structures (TLSs), characterized by densely packed CD20⁺ B cells in a germinal-center-like structure, have recently been recognized as immune-stimulating components within the tumor microenvironment. In contrast, cancer-associated fibroblasts (CAFs) are stromal cells expressing fibroblast-activating protein (FAP) involved in immunosuppression. Methods: In this retrospective study, 124 clinical samples from patients who underwent radical surgery for esophageal cancer at our institute were analyzed. We investigated whether TLSs could serve as a prognostic factor and examined their association with tumor microenvironment factors. Results: The presence of TLSs was an independent prognostic factor for overall and progression-free survival in multivariate analyses. A high level of TLS formation correlated with better nutritional status, fewer M2 macrophages, and greater plasma cell infiltration. Additionally, little TLS formation was observed in areas with abundant CAFs, and quantitative analyses revealed a significant negative correlation between TLSs and CAFs. Conclusions: TLSs enhance antitumor immunity via macrophages and plasma cells and can be a valuable prognostic indicator in patients undergoing surgery for esophageal cancer. Targeting CAFs may prove to be a promising therapeutic strategy to enhance tumor-immunity-related TLSs. Full article