Tumor-associated macrophages (TAMs) are key promoters of inflammatory breast cancer (IBC), the most aggressive form of breast cancer. The receptor tyrosine kinase AXL is highly expressed in various cancer types, including IBC, but its role in TAMs remains unexplored.

We examined the effects of AXL inhibitor TP-0903 on tumor growth and tumor microenvironment (TME) component M2 macrophages (CD206+) in IBC and triple-negative breast cancer mouse models using flow cytometry and immunohistochemical staining. Additionally, we knocked out AXL expression in human THP-1 monocytes and evaluated the effect of AXL signaling on immunosuppressive M2 macrophage polarization and IBC cell growth and migration. We then investigated the underlying mechanisms through RNA sequencing analysis. Last, we performed CIBERSORT deconvolution to analyze the association between AXL expression and tumor-infiltrating immune cell types in tumor samples from the Inflammatory Breast Cancer International Consortium.

We found that inhibiting the AXL pathway significantly reduced IBC tumor growth and decreased CD206+ macrophage populations within tumors. Mechanistically, our in vitro data showed that AXL promoted M2 macrophage polarization and enhanced the secretion of immunosuppressive chemokines, including CCL20, CCL26, and epiregulin, via the transcription factor STAT6 and thereby accelerated IBC cell growth and migration. RNA sequencing analysis further indicated that AXL signaling in immunosuppressive M2 macrophages regulated the expression of molecules and cytokines, contributing to an immunosuppressive TME in IBC. Moreover, high AXL expression was correlated with larger populations of immunosuppressive immune cells but smaller populations of immunoactive immune cells in tissues from patients with IBC.

AXL signaling promotes IBC growth by inducing M2 macrophage polarization and driving the secretion of immunosuppressive molecules and cytokines via STAT6 signaling, thereby contributing to an immunosuppressive TME. Collectively, these findings highlight the potential of targeting AXL signaling as a novel therapeutic approach for IBC that warrants further investigation in clinical trials.

Brain metastases (BrM) are the most common cancers in the brain and linked to poor prognosis. Given the high incidence and often limited treatment options, understanding the complexity of the BrM tumor microenvironment is crucial for the development of novel therapeutic strategies. We performed transcriptome-wide gene expression profiling combined with spatial immune cell profiling to characterize the tumor immune microenvironment in 95 patients with BrM from different primary tumors. We found that BrM from lung carcinoma and malignant melanoma showed overall higher immune cell infiltration as compared to BrM from breast carcinoma. RNA sequencing-based immune cell deconvolution revealed gene expression signatures indicative of tertiary lymphoid structures (TLS) in subsets of BrM, mostly from lung cancer and melanoma. This finding was corroborated by multiplex immunofluorescence staining of immune cells in BrM tissue sections. Detection of TLS signatures was more common in treatment-naïve BrM and associated with prolonged survival after BrM diagnosis in lung cancer patients. Our findings highlight the cellular diversity of the tumor immune microenvironment in BrM of different cancer types and suggest a role of TLS formation for BrM patient outcome.

Cancer remains a significant global health challenge, with the Cell Division Cycle 7 (CDC7) protein emerging as a potential therapeutic target due to its critical role in tumor proliferation, survival, and resistance. However, a comprehensive analysis of CDC7 across multiple cancers is lacking, and existing therapeutic options have come with limited clinical success. The aim of this is to integrate a comprehensive pan-cancer analysis of CDC7 with the identification of novel marine-derived inhibitors, bridging the understanding of CDC7's role as a prognostic biomarker and therapeutic target across diverse cancer types. In this study, we conducted a pan-cancer analysis of CDC7 across 33 tumor types using publicly available datasets to evaluate its expression, genetic alterations, immune interactions, survival, and prognostic significance. Additionally, a marine-derived compound library of 31,492 molecules was screened to identify potential CDC7 inhibitors using chemoinformatics and machine learning. The top candidates underwent rigorous evaluations, including molecular docking, pharmacokinetics, toxicity, Density Functional Theory (DFT) calculations, and Molecular Dynamics (MD) simulations. The findings revealed that CDC7 is overexpressed in several cancers and is associated with poor survival outcomes and unfavorable prognosis. Enrichment analysis linked CDC7 to critical DNA replication pathways, while its role in modulating tumor-immune interactions highlighted its potential as a target for immunotherapy. Among all tested compounds, Tetrahydroaltersolanol D (CMNPD21999) exhibited the strongest binding affinity and stability, along with better drug-likeness and zero toxicity. These attributes highlight its potential as a promising drug candidate for CDC7 inhibition and future cancer treatment development. Furthermore, additional in vitro and in vivo studies are required to confirm the effectiveness of this drug candidate against the CDC7 protein.

Understanding the impact of tertiary lymphoid structures (TLSs) on acral melanoma (AM) and the tumor microenvironment (TME) is critical. We analyzed TLS features in primary AM lesions from 46 patients and identified intratumoral TLSs (intra-TLSs) in 25 patients. Intra-TLS presence was significantly associated with improved overall survival. Hematoxylin and eosin staining and multiplex immunofluorescence revealed increased T-cell and CD8+ T-cell infiltration and fewer tumor-associated macrophages in the TME of intra-TLS patients. Transcriptomic analysis identified a TLS-associated Th1/B-cell gene set as a predictor of survival and immunotherapy response. These findings highlight the prognostic value of intra-TLSs in AMs and suggest that targeting TLS formation could enhance immunotherapy efficacy.

The lungs are constantly exposed to the external environment and a myriad of antigenic challenges within the air. Chronic exposure to allergens and other airborne antigens can result in the formation of lymphocyte aggregates in the lung, which can harbor ectopic germinal centers (GCs). After allergen exposure, GCs that form in the lung are much smaller and less densely packed with B cells than lymph node GCs. Despite this, ectopic lung GCs support somatic hypermutation and affinity-based maturation as in lymph node GCs, and export memory B cells (MBCs) directly into the lung tissue. This demonstrates that the lung can locally diversify B cell responses and supports the generation of tissue MBC populations in situ.

T follicular helper (Tfh) cells are integral to the germinal center (GC) response and the development of potent humoral immunity. By priming B cells, Tfh cells can initiate both extrafollicular and GC-dependent Ab responses. The dynamic physical interactions between Tfh and B cells constitute the primary platform for Tfh cells to provide essential "help" factors to B cells, as well as for reciprocal signaling from B cells to sustain the helper state of Tfh cells. In recent years, significant advancements have been made in understanding the diverse roles of Tfh cells across various diseases, particularly in cancer. Notably, beyond the classical GC-Tfh cells, it is increasingly recognized that the Tfh cell phenotype is highly heterogeneous and dynamic, which adds complexity to their roles in disease contexts. This review aims to encapsulate progress in Tfh cell biology, with a focus on their role in cancer and immunotherapy.

Tumor neoantigens, defined as tumor-specific antigens arising from somatic mutations, have shown great potential as targets for cancer vaccines in clinical studies. However, the number of neoantigens capable of effectively activating immune responses is quite limited. Over the past few decades, tumor neoantigen vaccines based on MHC-I epitopes that activate CD8+ T cells have been extensively studied. However, growing evidence suggests that CD4+ T cells are important in cancer immunotherapy. In contrast to CD8+ T cells, the receptors on CD4+ T cells exhibit a wider range of antigen peptide-MHC recognition, which can detect more tumor mutation antigens. In our earlier studies, a nitrated CD4+ T-cell epitope (NitraTh) was constructed as a novel CD4+ T-cell epitope that can enhance the immunogenicity of multiple tumor antigens. Therefore, we designed vaccines targeting MHC-II neoantigen epitopes using the nitrated T-cell epitope containing immunogenic amino acids. We found that vaccines conjugated with NitraTh exhibited enhanced immunogenicity. Crucially, the NitraTh-modified MHC-II tumor neoantigen vaccines increased the proportion of CD4+ T cells that infiltrate tumors and the spleen, elevated the expression of several cytokines with antitumor effects and facilitated the transformation of CD4+ T cells into Th1 cells, thereby reducing tumor growth. Additionally, the nitrated epitope has been shown to transform naïve CD4+ T cells into effector memory cells, thus facilitating enduring antitumor actions. The strategy of combining nitrated epitopes with MHC-II neoantigen epitopes confirms the significance of CD4+ T-cell immunity in cancer and may provide a novel approach for cancer vaccine design. SIGNIFICANCE STATEMENT: This study presents a novel design paradigm for tumor vaccines-combining MHC-II epitopes with nitrated CD4+ T-cell epitopes. This approach promotes the differentiation of CD4+ T cells toward a Th1 phenotype and generates long-lasting effector memory CD4+ T cells. Under the enhanced effects of CD4+ T cells, the vaccines we designed achieved superior antitumor efficacy and improved the immunosuppressive tumor microenvironment.

Tertiary lymphoid structures (TLSs) are ectopic immune cell clusters formed in nonlymphoid tissues affected by persistent inflammation, such as in cancer and prolonged infections. They have features of the structure and function of secondary lymphoid organs, featuring central CD20+ B cells, surrounded by CD3+ T cells, CD21+ follicular dendritic cells, and CD68+ macrophages, with a complex vascular system. TLS formation is governed by lymphotoxin-α1β2, TNF, and chemokines like CCL19, CCL21, and CXCL13, differing from secondary lymphoid organ development in developing later in life at sites of chronic inflammation. Their role in enhancing immune responses, particularly in the context of cancer, makes them a focal point in immunotherapy. This review discusses recent advances in TLS assessment that involves complex gene expression signatures, histological analysis, artificial intelligence, and spatial omics. The presence and maturity of TLS are associated with better outcomes in various cancers, acting as a biomarker for immunotherapy effectiveness. This review explores the structure, formation, and role of TLS in disease prognosis, including their roles in immunotherapy and non-immunotherapy treatments, highlighting a need to develop novel techniques for precise characterization of TLS as well as their significance as predictive biomarkers beyond traditional biomarkers.

Breast cancer (BC) ranks as one of the most prevalent malignancies among women globally. This study aimed to explore the involvement of neutrophil extracellular traps (NETs)-related genes (NETRGs) in BC pathogenesis, highlighting the critical role of NETs.

Differentially expressed NETRGs (DE-NETRGs) were identified by intersecting BC vs. control differentially expressed genes (DEGs) with the NETRG gene set from The Cancer Genome Atlas breast cancer (TCGA-BRCA) and GSE42568 datasets. Functional analysis elucidated their biological roles. Prognostic biomarkers were selected using least absolute shrinkage and selection operator (LASSO) and Cox regression, generating a predictive model, of which its prognostic predictive ability was evaluated through the Kaplan-Meier (KM) survival curve and receiver operating characteristic (ROC) curve, and verified it in the test set and the validation set. Subsequently, the clinicopathological features were incorporated into the risk model for Cox independent prognostic analysis, and a nomogram was constructed to verify the predictive performance of the model. Finally, the mechanism of action of the biomarkers in BC was explored through immune infiltration, immunotherapy, and drug sensitivity. The biomarker expression validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR).

Functional analysis revealed 37 DE-NETRGs associated with leukocyte migration and the Interleukin (IL)-17 signaling pathway. Four biomarkers [F2RL2, AZU1, IL33, neutrophil elastase (ELANE)] were used to construct the prognostic model and it was validated by the test set and the validation set. The KM curve showed significant differences in prognosis between the high- and low-risk group, while the ROC curve showed that the model had good predictive performance. Radiation, age, tumor stage, pathologic N, and risk scores were identified as independent prognostic factors. Subgroups based on risk scores exhibited distinct immune cell infiltration patterns, with the risk score positively correlated with M0 macrophages and resting mast cells. The high-risk group demonstrated lower Tumor Immune Dysfunction and Exclusion (TIDE) scores. Drug sensitivity varied between risk subgroups, and qRT-PCR confirmed the expression of ELANE and IL33.

This study has reported four biomarkers related to BC prognosis, namely F2RL2, AZU1, IL33, and ELANE. Our study has offered new potential biomarkers for prognosis and has identified therapeutic targets for the treatment and prognosis prediction in BC patients.

Lag3 and PD-1 are immune checkpoints that regulate T cell responses and are current immunotherapy targets. Yet how they function to control early stages of CD4+ T cell activation remains unclear.

Here, we show that the PD-1 and Lag3 pathways exhibit layered control of the early CD4+ T cell activation process, with the effects of Lag3 more pronounced in the presence of PD-1 pathway co-blockade (CB). RNA sequencing revealed that CB drove an early NFAT-dependent transcriptional profile, including promotion of ICOShi T follicular helper cell differentiation.

NFAT pathway inhibition abolished CB-induced upregulation of NFAT-dependent co-receptors ICOS and OX40, whilst unaffecting the NFAT-independent gene Nr4a1. Mechanistically, Lag3 and PD-1 pathways functioned additively to regulate the duration of T cell receptor signals during CD4+ T cell re-activation. Phenotypic changes in peripheral blood CD4+ T cells in humans on anti-Lag3 and anti-PD-1 combination therapy revealed upregulation of genes encoding ICOS and OX40 on distinct CD4+ T cell subsets, highlighting the potential translational relevance of our findings.

Our data therefore reveal that PD-1 and Lag3 pathways converge to additively regulate TCR signal duration and may preferentially control NFAT-dependent transcriptional activity during early CD4+ T cell re-activation.

The widespread use of immune checkpoint inhibitors (anti-CTLA4 or PD-1) has opened a new chapter in tumor immunotherapy by providing long-term remission for patients. Unfortunately, however, these agents are not universally available and only a minority of patients respond to them. Therefore, there is an urgent need to develop novel therapeutic strategies targeting other co-inhibitory molecules. However, comprehensive information on the expression and prognostic value of co-inhibitory molecules, including co-inhibitory receptors and their ligands, in different cancers is not yet available.

We investigated the expression, correlation, and prognostic value of co-inhibitory molecules in different cancer types based on TCGA, UCSC Xena, TIMER, CellMiner datasets. We also examined the associations between the expression of these molecules and the extent of immune cell infiltration. Besides, we conducted a more in-depth study of VISTA.

The results of differential expression analysis, correlation analysis, and drug sensitivity analysis suggest that CTLA4, PD-1, TIGIT, LAG3, TIM3, NRP1, VISTA, CD80, CD86, PD-L1, PD-L2, PVR, PVRL2, FGL1, LGALS9, HMGB1, SEMA4A, and VEGFA are associated with tumor prognosis and immune cell infiltration. Therefore, we believe that they are hopefully to serve as prognostic biomarkers for certain cancers. In addition, our analysis indicates that VISTA plays a complex role and its expression is related to TMB, MSI, cancer cell stemness, DNA/RNA methylation, and drug sensitivity.

These co-inhibitory molecules have the potential to serve as prognostic biomarkers and therapeutic targets for a broad spectrum of cancers, given their strong associations with key clinical metrics. Furthermore, the analysis results indicate that VISTA may represent a promising target for cancer therapy.

Tumor-infiltrating lymphocytes (TILs) are associated with lymph node metastasis and prognosis in breast cancer. Therefore, we explored the value of TILs in predicting sentinel lymph node metastasis (SLNM) in patients with early-stage (cT1-2N0) breast cancer and provided a new method for preoperative assessment of SLNM status.

This study included 337 patients with early-stage breast cancer who underwent surgery at our hospital from January 2022 to December 2023. The expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 in the patients was assessed using immunohistochemistry (IHC). TILs in the core needle biopsy samples were evaluated histopathologically, and patients were divided into high and low TILs groups based on the density of TILs. Statistical analysis was conducted, and a predictive model was established.

The study found that patients with high TILs had a significantly lower rate of SLNM compared to those with low TILs (P < 0.001). The cT stage and the level of TILs were identified as independent predictive factors for SLNM. The ROC curve analysis indicated that the density of TILs has good predictive efficacy for SLNM. Based on the results of the multivariate regression analysis, a nomogram predictive model for SLNM was constructed.

Our study showed that the density of TILs and cT stage are independent predictive factors for SLNM in early-stage (cT1-2N0) breast cancer, and the predictive effect of TILs density on SLNM is significant in Luminal and triple-negative breast cancers.

Immune checkpoint blockade (ICB) inhibits tumor immune escape and has significantly advanced tumor therapy. However, ICB benefits only a minority of patients treated and may lead to many immune-related adverse events. Therefore, identifying factors that can predict treatment outcomes, enhance synergy with ICB, and mitigate immune-related adverse events is urgently needed.

Tertiary lymphoid structures (TLS) are ectopic lymphoid tissues that arise from the tumor periphery. They have been found to be associated with better prognosis and improved clinical outcomes after ICB therapy. TLS may help address the problems associated with ICB. The multiple mechanisms of action between TLS and ICB remain unknown. This paper described potential mechanisms of interaction between the two and explored their potential applications.

Breast cancer is the most common type of cancer in women and the second leading cause of death by cancer. Despite recent advances, the mortality rate remains high, underlining the need to develop new therapeutic approaches. The complex interaction between cancer cells and the tumor microenvironment (TME) is crucial in determining tumor progression, therapy response, and patient prognosis. Understanding the role of immune cells in carcinogenesis and tumor progression can help improve targeted therapeutic options, increasing the likelihood of a favorable prognosis. Therefore, this review aims to critically analyze the complex interaction between tumor cells and immune cells, emphasizing the clinical and therapeutic implications. Additionally, we explore advances in immunotherapies, with a focus on immune checkpoint inhibitors.

T follicular helper (TFH) cells, a subset of CD4+Th cells, play a critical role in B cell activation, proliferation, and differentiation primarily within B follicles in secondary lymphoid organs, essential processes for effective antibody responses. TFH cells are also implicated in various conditions, including autoimmune diseases, cancer, infectious diseases, allergies, and vaccine reactions. Despite their broad impact, a review of the literature on TFH cells and tumors has not been conducted. We aimed to fill this gap by providing a detailed analysis of the research landscape concerning TFH cells and tumors.

We conducted a bibliometric analysis of literature on TFH cells and tumors from 2012 to 2024 using the Web of Science Core Collection (WoSCC). For an analysis of the global research landscape, we employed VOSviewer (version 1.6.20), CiteSpace 6.2.R6 software, and the "bibliometric" package in R language (version 4.3.2) to evaluate data on countries/regions, authors and cited authors, institutions, journals, references, and keywords. We also conducted a systematic review to summarize the global research trends, prospects, and hotspots in this field.

Our analysis included contributions from 60 countries/regions, 7,864 authors, 35,853 cited authors, 1,756 institutions, 385 academic journals, 50883 references, 222 keywords, and 1,181published papers. Over the past decade, the volume of research on TFH cells and tumors had consistently increased. China published the most papers, more than double that of the United States. The top 2 authors ranked by publication volume were Gaulard, Philippe (14 articles, 379 citations), and De leval, Laurence (12 articles, 236 citations) Notably, 9 of the top 10 most published institutions were from China. Frontiers in Immunology and Immunity were the leading journals in publications and citations. A cluster analysis revealed a shift in research focus from "expression","B cells" and "survival" to "tumor microenvironment", "tumor infiltrating immune cells" and "immune infiltration" in recent years.

This bibliometric analysis suggests that TFH cells hold significant research value and potential clinical applications in tumor immunotherapy. Moreover, the bibliometric analysis offers valuable references and guidance for related research endeavors. It also points out the prevailing issues and challenges in TFH cell research, and underscores the need for further basic and clinical research to advance the related fields.

This study aimed to investigate the effects of silicone implants on the incidence of breast cancer in rats, as well as their impact on immune surveillance mechanisms. Female SD rats were divided into three groups: a Placebo Surgery Group (PSG), a Thoracic Implant Group (TIG), and a Back Implant Group (BIG). Following the corresponding surgical procedures, we measured Secretoglobin Family 2A, Member 2(SCGB2A2) and Mucin-1 (MUC1) antigen levels using ELISA, and statistical analyses were conducted to evaluate immune responses. The N-Methyl-N-Nitrosourea(MNU)-induced breast cancer model and pathological analyses indicated that the incidence of breast cancer in the thoracic implant group was lower, suggesting that silicone implants may reduce the risk of breast cancer. Additionally, laser speckle blood flow imaging and immunohistochemical analysis revealed blood perfusion in the implant capsule area and an active response of immune cells, indicating that immune surveillance may exert local effects. These findings provide the first evidence of a relationship between tumor antigens, silicone implants, and breast cancer incidence, offering a new immunological perspective on the safety of silicone implants.

Tertiary lymphoid structures (TLSs) are de novo ectopic lymphoid aggregates that regulate immunity in chronically inflamed tissues, including tumours. Although TLSs form due to inflammation-triggered activation of the lymphotoxin (LT)-LTβ receptor (LTβR) pathway1, the inflammatory signals and cells that induce TLSs remain incompletely identified. Here we show that interleukin-33 (IL-33), the alarmin released by inflamed tissues2, induces TLSs. In mice, Il33 deficiency severely attenuates inflammation- and LTβR-activation-induced TLSs in models of colitis and pancreatic ductal adenocarcinoma (PDAC). In PDAC, the alarmin domain of IL-33 activates group 2 innate lymphoid cells (ILC2s) expressing LT that engage putative LTβR+ myeloid organizer cells to initiate tertiary lymphoneogenesis. Notably, lymphoneogenic ILC2s migrate to PDACs from the gut, can be mobilized to PDACs in different tissues and are modulated by gut microbiota. Furthermore, we detect putative lymphoneogenic ILC2s and IL-33-expressing cells within TLSs in human PDAC that correlate with improved prognosis. To harness this lymphoneogenic pathway for immunotherapy, we engineer a recombinant human IL-33 protein that expands intratumoural lymphoneogenic ILC2s and TLSs and demonstrates enhanced anti-tumour activity in PDAC mice. In summary, we identify the molecules and cells of a druggable pathway that induces inflammation-triggered TLSs. More broadly, we reveal a lymphoneogenic function for alarmins and ILC2s.

With the incorporation of immune checkpoint inhibitors into the treatment of endometrial cancer (EC), a deeper understanding of the tumor immune microenvironment is critical. Tertiary lymphoid structures (TLSs) are considered favorable prognostic factors for EC, but the significance of their spatial distribution remains unclear. B cell receptor repertoire analysis performed using six TLS samples located at various distances from the tumor showed that TLSs in distal areas had more shared B cell clones with tumor-infiltrating lymphocytes. To comprehensively investigate the distribution of TLSs, we developed an artificial intelligence model to detect TLSs and determine their spatial locations in whole-slide images. Our model effectively quantified TLSs, and TLSs were detected in 69% of the patients with EC. We identified them as proximal or distal to the tumor margin and demonstrated that patients with distal TLSs (dTLSs) had significantly prolonged overall survival and progression-free survival (PFS) across multiple cohorts [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.36-0.88; p = 0.01 for overall survival; HR, 0.58; 95% CI, 0.40-0.84; p = 0.004 for PFS]. When analyzed by molecular subtype, patients with dTLSs in the copy-number-high EC subtype had significantly longer PFS (HR, 0.51; 95% CI, 0.29-0.91; p = 0.02). Moreover, patients with dTLSs had a higher response rate to immune checkpoint inhibitors (87.5 vs. 41.7%) and a trend toward improved PFS. Our findings indicate that the functions and prognostic implications of TLSs may vary with their locations, and dTLSs may serve as prognostic factors and predictors of treatment efficacy. This may facilitate personalized therapy for patients with EC.

The prognosis for muscle-invasive bladder cancer (MIBC) remains poor, and reliable prognostic markers have yet to be identified. Tertiary lymphoid structures (TLS) have been associated with favorable outcomes in certain cancers. However, the relationship between TLS and MIBC remains unclear. A multi-omics approach is utilized, leveraging single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and immunohistochemistry, to investigate the roles of B cells and TLS in MIBC. These findings indicate that elevated levels of B cells and TLS correlate with improved prognoses in patients with MIBC, aligning with the robust antitumor immune responses observed in the TLS region. From a mechanistic perspective, CXCL13 serves as a critical cytokine for TLS formation in MIBC, primarily secreted by clonally expanded CXCL13+ T cells. This cytokine interacts with the CXCR5 receptor on NR4A2+ B cells, promoting TLS development. Plasma cells arising within the TLS microenvironment predominantly produce the IGHG antibody, potentially enhancing the phagocytic capabilities of C1QC+ macrophages. From an application standpoint, a TLS-specific gene signature is developed that effectively predicts outcomes in MIBC and other cancers. This study highlights the prognostic potential of TLS in MIBC and reveals immune mechanisms, offering insights for personalized treatment strategies.

Upper aerodigestive tract cancers are prevalent, with a global incidence surpassing 500,000 new cases in 2018. Among these, oral squamous cell carcinomas (OSCC) constitute the majority. OSCC has a low 5-year survival rate due to late-stage diagnosis. Risk factors include alcohol and tobacco use. However, non-smokers and non-drinkers are also affected, especially young patients with tongue cancer. The impact of tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) on OSCC prognosis remains debated. Remarkably, Tertiary Lymphoid Structures (TLS) identified in solid tumors have shown associations with favorable outcomes, yet their prognostic significance in OSCC remains understudied.

Thus, this systematic review aims to explore the value of TLS in OSCC reported in the literature.

A scoping review was conducted and six retrospective cohort studies involving 1,203 patients met the inclusion criteria.

Predominantly male patients, with an average age of 49.3 years were included. Immunohistochemistry was the primary method to identify TLS, present in 21% up to 100% of cases. TLS were predominantly located in the peri-tumoral area (75.4%-84.8%) compared to the intra-tumoral area (33.8%-33.9%). Our review shows that the presence of TLS is associated with improved survival in OSCC.

However, variations in TLS detection and classification methods across studies introduce potential biases, hindering direct comparisons between findings. For instance, reports that are based solely on examining HES-stained slides for TLS identification may raise reliability concerns. Standardization of methodologies is imperative to ensure consistency in criteria utilization, thereby facilitating meaningful data comparisons.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023428010, PROSPERO (CRD42023428010).

Nanoparticle technology has revolutionized breast cancer treatment by offering innovative solutions addressing the gaps in traditional treatment methods. This paper aimed to comprehensively explore the historical journey and advancements of nanoparticles in breast cancer treatment, highlighting their transformative impact on modern medicine. The discussion traces the evolution of nanoparticle-based therapies from their early conceptualization to their current applications and future potential. We initially explored the historical context of breast cancer treatment, highlighting the limitations of conventional therapies, such as surgery, radiation, and chemotherapy. The advent of nanotechnology has introduced a new era characterized by the development of various nanoparticles, including liposomes, dendrimers, and gold nanoparticles, designed to target cancer cells with remarkable precision. We further described the mechanisms of action for nanoparticles, including passive and active targeting, and reviewed significant breakthroughs and clinical trials that have validated their efficacy. Current applications of nanoparticles in breast cancer treatment have been examined, showcasing clinically approved therapies and comparing their effectiveness with traditional methods. This article also discusses the latest advancements in nanoparticle research, including drug delivery systems and combination therapy innovations, while addressing the current technical, biological, and regulatory challenges. The technical challenges include efficient and targeted delivery to tumor sites without affecting healthy tissue; biological, such as potential toxicity, immune system activation, or resistance mechanisms; economic, involving high production and scaling costs; and regulatory, requiring rigorous testing for safety, efficacy, and long-term effects to meet stringent approval standards. Finally, we have explored emerging trends, the potential for personalized medicine, and the ethical and social implications of this transformative technology. In conclusion, through comprehensive analysis and case studies, this paper underscores the profound impact of nanoparticles on breast cancer treatment and their future potential.

In situ vaccination (ISV) triggers antitumor immune responses using the patient's own cancer antigens, yet limited neoantigen release hampers its efficacy. Our novel combination therapy involves low-dose local cisplatin followed by ISV with a TLR7/8/9 agonist formulation (CR108), in which CR108 boosts and sustains the antitumor responses induced by the cisplatin-released neoantigens. In mouse models, the cisplatin+CR108 combination significantly outperformed cisplatin or CR108 alone in abrogating established 4T1 and B16 tumors. The synergistic antitumor effects of cisplatin and CR108 were accompanied by markedly increased tumor tertiary lymphatic structures (TLS) formation, higher levels of type I and III interferons and TNF-α in serum, augmented T and B lymphocyte infiltration, antigen-presenting cell activation, as well as reduced functionally of exhausted T cells. Single-cell sequencing analysis uncovered a potential pathway for TLS to serve as a reservoir for functional antitumor effector T cells. Furthermore, cisplatin+CR108 combo therapy, but neither cisplatin nor CR108 alone, effectively inhibited the growth of treated 4T-1 tumor in an effector T cell-dependent manner. Notably, the combo therapy also suppressed the growth of distant untreated 4T-1 tumors, demonstrating systemic antitumor effects. Moreover, combo-therapy led to full regression of 4T-1 tumors in a large percentage of mice, who became strongly resistant to secondary tumor challenge, a clear indication of antitumor immunological memory. The cisplatin+CR108 combo therapy holds promise in converting "cold" tumors into "hot" ones and eliciting robust antitumor immune responses in vivo.

There is still no consensus regarding the correlation between TLS and the prognosis of lung cancer patients. This meta-analysis aimed to investigate the association between TLS and prognosis in patients with lung cancer. In addition, the prognostic value of TLS for the efficacy of immunotherapy was also studied.

We systematically searched the PubMed, Embase, Cochrane Library, and Web of Science databases from database inception to November 1, 2023. The hazard ratio (HR) and corresponding 95% confidence interval (CI) for overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), progression-free survival (PFS) and disease-specific survival (DSS) were extracted and merged with STATA 14.0. The study protocol was registered with PROSPERO (CRD42024502483).

A total of 17 studies comprising 4291 patients were included in this meta-analysis. The pooled results revealed that high TLS/TLS + patients had better OS (HR = 0.66, 95% CI: 0.50-0.88), DFS (HR = 0.46, 95% CI: 0.33-0.64), DSS (HR = 0.48, 95% CI: 0.39-0.60) and RFS (HR = 0.43, 95% CI: 0.33-0.57). High TLS/TLS + patients tended to have longer PFS than low TLS/TLS + patients (HR = 0.68, 95% CI: 0.35-1.35). Interestingly, in the Asia subgroup, the association between TLS and survival was especially significant, whereas there was no significant difference in Europe. In addition, in patients who received neoadjuvant chemoimmunotherapy, high TLS/TLS + was associated with prolonged DFS (HR = 0.21, 95%CI: 0.05-0.93).

High TLS/TLS + was associated with improved survival and an improved response to neoadjuvant chemoimmunotherapy in lung cancer patients, suggesting that TLS may be a prognostic biomarker and may also be a promising predictive marker for the response to neoadjuvant chemoimmunotherapy. However, additional original studies are needed to further confirm these findings.

B cells have emerged as central players in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). However, although there is clear evidence for their involvement in cancer immunity, scanty data exist on the characterization of B cell phenotypes, bioenergetic profiles and possible interactions with T cells in the context of NSCLC. In this study, using polychromatic flow cytometry, mass cytometry, and spatial transcriptomics we explored the intricate landscape of B cell phenotypes, bioenergetics, and their interaction with T cells in NSCLC. Our analysis revealed that TME contains diverse B cell clusters, including VISTA+ Bregs, with distinct metabolic and functional profiles. Target liquid chromatography-tandem mass spectrometry confirmed the expression of VISTA on B cells. VISTA+ Bregs displayed high metabolic demand and were able to produce different cytokines, including interleukin (IL)-10, transforming growth factor (TGF)-β, IL-6, tumor necrosis factor (TNF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Spatial analysis showed colocalization of B cells with CD4+/CD8+ T lymphocytes in TME. The computational analysis of intercellular communications that links ligands to target genes, performed by NicheNet, predicted B-T interactions via VISTA-PSGL-1 axis. Colocalization analyses revealed that PSGL-1 T cells and VISTA+ B cells are adjacent in the TME. Notably, tumor infiltrating CD8+ T cells expressing PSGL-1 exhibited enhanced metabolism and cytotoxicity. In NSCLC patients, prediction analysis performed by PENCIL revealed the presence of an association between PSGL-1+CD8+ T cells and VISTA+ Bregs with lung recurrence. Our findings suggest a potential interaction between Bregs and T cells through the VISTA-PSGL-1 axis, that could influence NSCLC recurrence.

Tertiary lymphoid structures (TLSs) are organized ectopic lymphoid aggregates within the tumor microenvironment that serve as crucial sites for the development of adaptive antitumor cellular and humoral immunity. TLSs have been consistently documented in numerous cancer types, correlating with improved prognosis and enhanced responses to immunotherapy, especially immune-checkpoint blockade (ICB). Given the potential role of TLSs as predictive biomarkers for the efficacy of ICB in cancer patients, the therapeutic manipulation of TLSs is gaining significant attention as a promising avenue for cancer treatment. Herein, we comprehensively review the composition, definition, and detection methods of TLSs in humans. We also discuss the contributions of TLSs to antitumor immunity, their prognostic value in cancer patients, and their association with therapeutic response to ICB-based immunotherapy. Finally, we present preclinical data supporting the potential of therapeutically manipulating TLSs as a promising approach for innovative cancer immunotherapy.

Breast cancer is a heterogeneous malignant disease with a varying prognosis and is classified into four molecular subtypes. It remains one of the most prevalent cancers globally, with the tumor microenvironment playing a critical role in disease progression and patient outcomes.

This study evaluated tumor samples from 40 female patients with luminal A and B breast cancer, utilizing flow cytometry to phenotypically characterize the immune cells and tumor cells present within the tumor tissue.

The luminal B-like tumor samples exhibited increased infiltration of CD4+ cells, regulatory T cells (Tregs), and Th17 cells and decreased levels of NK cells, γδ T cells, Th1 cells, and follicular T cells, which is indicative of a more immunosuppressive tumor microenvironment.

These findings suggest that luminal B-like tumors have a microenvironment that is less supportive of effective anti-tumor immune responses compared to luminal A tumors. This study enhances the understanding of the immunological differences between luminal subtypes of breast cancer and identifies potential new therapeutic targets and biomarkers that could drive advancements in precision medicine for breast cancer management.

Gastric cancer is a common malignant tumor of the digestive tract, and its treatment remains a significant challenge. In recent years, the role of various immune cells in the tumor microenvironment in cancer progression and treatment has gained increasing attention. Immunotherapy, primarily based on immune checkpoint inhibitors, has notably improved the prognosis of patients with gastric cancer; however, challenges regarding therapeutic efficacy persist. Histological features within the tumor microenvironment, such as tertiary lymphoid structures (TLSs), tumor-infiltrating lymphocytes, and the proportion of intratumoral stroma, are emerging as potentially effective prognostic factors. In gastric cancer, TLSs may serve as local immune hubs, enhancing the ability of immune cells to interact with and recognize tumor antigens, which is closely linked to the effectiveness of immunotherapy and improved survival rates in patients. However, the specific cell type driving TLS formation in tumors has not yet been elucidated. Mature TLSs are B-cell regions containing germinal centers. During germinal center formation, B cells undergo transformations to become mature cells with immune function, exerting anti-tumor effects. Therefore, targeting B cells within TLSs could provide new avenues for gastric cancer immunotherapy. This review, combined with current research on TLSs and B cells in gastric cancer, elaborates on the relationship between TLSs and B cells in the prognosis and immunotherapy of patients with gastric cancer, aiming to provide effective guidance for precise immunotherapy.

Cancer-associated Fibroblasts (CAFs) have emerged as critical regulators of anti-tumour immunity, with both beneficial and detrimental properties that remain poorly characterised. To investigate this, we performed single-cell and spatial transcriptomic analysis, comparing head & neck squamous cell carcinoma (HNSCC) subgroups, which although heterogenous, can be considered broadly immune-hot and immune-cold (human papillomavirus [HPV]+ve and HPV-ve tumours respectively). This identified six fibroblast subpopulations, including two with immunomodulatory gene expression profiles (IL-11 + inflammatory [i]CAF and CCL19 + fibroblastic reticular cell [FRC]-like). IL-11 + iCAF were spatially associated with inflammatory monocytes and regulated in vitro through synergistic activation of canonical NF-κB signalling by IL-1β and TNF-α. FRC-like were enriched in immune-hot HPV+ve tumours, associated with CD4 + T-cells and B-cells in tertiary lymphoid structures and regulated through non-canonical NF-κB signalling via lymphotoxin. Pan-cancer analysis revealed several 'iCAF' subgroups present in both normal and cancer tissues; IL11 + iCAF were found in cancers from the gastrointestinal (GI) tract and transcriptomically distinct from iCAFs previously described in pancreatic and breast cancers with greater inflammatory properties; FRC-like fibroblasts were present at low frequencies in all tumour types, and were associated with significantly better survival in patients receiving checkpoint immunotherapy. This work clarifies and expands current literature on immunomodulatory CAFs, highlighting links with important immunological niches.

The T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), a newly discovered checkpoint, is characterized by its elevated expression on CD4 + T cells, CD8 + T cells, natural killer (NK) cells, regulatory T cells (Tregs), and tumor-infiltrating lymphocytes (TILs). Research to date has been shown that TIGIT has been linked to exhaustion of NK cell both and T cells in numerous cancers. CD155, being the specific ligand of TIGIT in humans, emerges as a key target for immunotherapy owing to its crucial interaction with TIGIT. Furthermore, numerous studies have demonstrated that the combination of TIGIT with other immune checkpoint inhibitors (ICIs) and/or traditional treatments elicits a potent antitumor response in colorectal cancer (CRC). This review provides an overview of the structure, function, and signaling pathways associated with TIGIT across multiple immune system cell types. Additionally, focusing on the role of TIGIT in the progression of CRC, this study reviewed various studies exploring TIGIT-based immunotherapy in CRC.

IntroductionRenal cancer, particularly Kidney Renal Clear Cell Carcinoma (KIRC), remains a major clinical challenge due to its aggressive nature and poor prognosis. Identifying reliable biomarkers for tumor progression and survival is critical for improving patient outcomes. This study aimed to investigate the role of Centromere Protein F (CENPF) as a potential prognostic biomarker for renal cancer.MethodData from the TCGA database, including Kidney Chromophobe (KICH), Kidney Renal Papillary Cell Carcinoma (KIRP), and KIRC, were analyzed to identify differentially expressed genes. Molecular Complex Detection (MCODE) was used to identify significant gene modules among upregulated genes, and univariate Cox regression analyses assessed the prognostic value of hub genes. Retrospective qPCR was conducted on tissue and plasma samples from KIRC patients to validate findings. Single-cell sequencing data from the GSE159115 dataset were analyzed, and the CIBERSORT algorithm was applied to evaluate the composition of tumor immune infiltrating cells (TIICs).ResultsCENPF was identified as a hub gene significantly upregulated in renal cancer subtypes, with overexpression linked to worse survival outcomes in KIRC patients. Retrospective qPCR confirmed high CENPF expression was associated with poorer prognosis. Single-cell sequencing revealed that CENPF is predominantly expressed in T-cell clusters. TIIC analysis showed a negative correlation between CENPF and resting mast cells, but positive correlations with follicular helper T-cells and memory-activated CD4T-cells. Prognostic analysis indicated that high follicular helper T-cell expression predicted poorer survival, while high plasma cell expression correlated with better outcomes.ConclusionCENPF plays a critical role in tumor progression and the modulation of the tumor immune microenvironment in KIRC. These findings suggest that CENPF could serve as a valuable prognostic biomarker and potential target for therapeutic intervention in renal cancer.

Quantification of lymphoid aggregates including tertiary lymphoid structures (TLS) with germinal centers in histology images of cancer is a promising approach for developing prognostic and predictive tissue biomarkers. In this article, we provide recommendations for identifying lymphoid aggregates in tissue sections from routine pathology workflows such as hematoxylin and eosin staining. To overcome the intrinsic variability associated with manual image analysis (such as subjective decision-making, attention span), we recently developed a deep learning-based algorithm called HookNet-TLS to detect lymphoid aggregates and germinal centers in various tissues. Here, we additionally provide a guideline for using manually annotated images for training and implementing HookNet-TLS for automated and objective quantification of lymphoid aggregates in various cancer types.