Understanding both local and systemic immunity is essential to optimizing the effectiveness of immunotherapy. However, the dynamic alterations in systemic immunity during tumor development are yet to be clearly defined. Here, we identified a previously unrecognized connection that bridges the interaction between the spleen and tumor through erythroid progenitor cells (EPCs), which suppress tumor immunity and promote tumor progression. We performed the single-cell RNA-seq and RNA-seq to demonstrate the presence of EPCs and identify the characteristic and an immunomodulatory role of EPCs during tumor progression. These tumor-hijacked EPCs proliferate in situ in spleens and impaired systemic and local antitumor response through the interaction between tumor and spleen. Specifically, the splenic CD45- EPCs secreted heparin-binding growth factor to regulate PD-L1-mediated immunosuppression of splenic CD45+ EPCs. Educated CD45+ EPCs from the spleen then migrated to the tumors via the CCL5/CCR5 axis, thereby weakening local antitumor immunity. Consequently, targeting EPCs not only revitalized antitumor immunity but also improved the anti-PD-L1 effect by promoting intratumoral T cell infiltration. Importantly, CD45+ EPCs are associated with immunosuppression and reduced survival in patients with head and neck squamous cell carcinoma. Collectively, these findings reveal the role of EPCs in orchestrating the interaction between the spleen and tumor, which could have significant implications for the development of more effective cancer immunotherapy.

Oral squamous cell carcinoma (OSCC) is frequently observed as the predominant malignancy affecting the oral cavity, with distant metastasis greatly affecting the treatment and long-term outlook for individuals with OSCC. Immune checkpoint inhibitors are a highly promising cancer treatment strategy currently available, but they are only successful for a small fraction of individuals with OSCC. Due to the insufficient understanding of the immune escape mechanisms in OSCC, coupled with disappointing treatment outcomes for patients with highly heterogeneous metastatic diseases, there is an urgent need for further exploration of immune target therapy strategies. This review discusses the mechanisms by which OSCC cells evade immune surveillance and attack, focusing on four aspects: metastasis-initiating cells, increased immune suppression, immune escape of dormant cells, and immune stromal crosstalk during metastasis. Additionally, we explore new areas in immune therapy for OSCC. In summary, our investigation offers fresh perspectives on the relationship between the tumor microenvironment and immune molecules, highlighting the importance of overcoming immune evasion for the development of novel therapies to manage OSCC metastasis and enhance patient outcomes.

Network biology facilitates a better understanding of complex diseases. Single-sample networks retain individual information and have the potential to distinguish disease status. Previous studies mainly used bulk RNA sequencing data to construct single-sample networks, but different cell types in the tissue microenvironment perform significantly different functions. In this study, we investigated whether network topology features of cell-type-specific networks varied in different pathological states at the individual level. Protein-protein interaction network (PPI) and co-expression network of cancer and ulcerative colitis were established using four publicly single-cell RNA sequencing (scRNA-seq) datasets. We analyzed cell-cell interactions of epithelial cells and immune cells using CellChat R package. Network topology changes between normal tissues and pathological tissues were analyzed using Cytoscape software and QUACN R package. Results showed cell-cell interactions of epithelial cells were enhanced in carcinoma and adenoma. The average number of neighbors and graphindex of co-expression network increased in epithelial cells of adenoma, carcinoma and paracancer compared with normal tissues. The co-expression network density of T cells in tumors was significantly higher than that in normal tissues. The co-expression network complexity of epithelial cells in the benign tissues was associated with the grade group of paired tumors. This study suggests topological properties of cell-type-specific individual network vary in different pathological states, providing an insight into understanding complex diseases.

Preterm neonates die at a significantly higher rate from sepsis than full-term neonates, attributable to their dysregulated immune response. In addition to tissue destruction caused directly by bacterial invasion, an overwhelming cytokine response by the immune cells to bacterial antigens also results in collateral damage. Sepsis leads to decreased gene expression of a critical transcription factor, Krüppel-like factor-2 (KLF2), a tonic repressor of myeloid cell activation. Using a murine model of myeloid- Klf2 deletion, we show that loss of KLF2 is associated with decreased survival after endotoxemia in a developmentally dependent manner, with increased mortality at postnatal day 4 (P4) compared to P12 pups. This survival is significantly increased by neutrophil depletion. P4 knockout pups have increased pro-inflammatory cytokine levels after endotoxemia compared to P4 controls or P12 pups, with significantly increased levels of IL-1β, a product of the activation of the NLRP3 inflammasome complex. Loss of myeloid-KLF2 at an earlier postnatal age leads to a greater increase in NLRP3 priming and activation and greater IL-1β release by BMNs. Inhibition of NLRP3 inflammasome activation by MCC950 significantly increased survival after endotoxemia in P4 pups. Transcriptomic analysis of bone marrow neutrophils showed that loss of myeloid-KLF2 is associated with gene enrichment of pro-inflammatory pathways in a developmentally dependent manner. These data suggest that targeting KLF2 could be a novel strategy to decrease the pro-inflammatory cytokine storm in neonatal sepsis and improve survival in neonates with sepsis.

KLF2 regulates the developmental response to endotoxin in neonatal mice through the NLRP3 inflammasome signaling pathway.

Recently, studies have reported that pan-viral serology signatures may be predictive for liver cancer development. However, whether these same findings are observed for prospective studies has not been previously investigated. The nested case-control analysis included 191 persons who developed liver cancer and 382 controls from the PLCO prospective cohort. The presence of circulating antibodies, measured by VirScan, was determined in serum samples obtained at study recruitment. The presence of antibodies was compared between cases and controls using multivariable conditional logistic regressions, and prediction models were used to estimate whether exposures predicted liver cancer development. No significant associations were found between antibodies to viruses, bacteria or allergens and liver cancer risk after adjustment for multiple testing. The agent most significantly associated with risk was hepatitis C virus (HCV), but it was only detected among 23 participants (odds ratio (OR): 3.98; 95% confidence intervals (CI):1.59-9.99; p = 0.0032, False Discovery Rate (FDR) = 0.35). In prediction models based on 109 antibody features, no associations with liver cancer risk were observed (area under the curve [AUC]: 0.52-0.54). In analyses restricted to the most common type of liver cancer, hepatocellular carcinoma, the association with HCV was stronger (OR: 23.16, 95% CI: 4.55-117.68; FDR p-value = 0.0016), although prediction models based on all detected antibodies were similar (AUC = 0.55; 95% CI:0.43-0.68). Antibodies to no infectious agents, other than HCV, were found to be prospectively associated with liver cancer risk. The utility of using an antibody exposure signature prospectively for liver cancer development needs to be further explored.

Resistance to immune checkpoint inhibitors (ICI) is common, even in tumors with T-cell infiltration. We thus investigated consequences of ICI-induced T-cell infiltration in the microenvironment of resistant tumors. T cells and neutrophil numbers increased in ICI-resistant tumors following treatment, in contrast to ICI-responsive tumors. Resistant tumors were distinguished by high expression of IL1 receptor 1, enabling a synergistic response to IL1 and TNFα to induce G-CSF, CXCL1, and CXCL2 via NF-κB signaling, supporting immunosuppressive neutrophil accumulation in tumor. Perturbation of this inflammatory resistance circuit sensitized tumors to ICIs. Paradoxically, T cells drove this resistance circuit via TNFα both in vitro and in vivo. Evidence of this inflammatory resistance circuit and its impact also translated to human cancers. These data support a mechanism of ICI resistance, wherein treatment-induced T-cell activity can drive resistance in tumors responsive to IL1 and TNFα, with important therapeutic implications.

Tumour immune macroenvironment is comprised of tumour and surrounding organs responding to tumourigenesis and immunotherapy. The lack of comprehensive analytical methods hinders its application for prediction of survival and treatment response in colorectal cancer (CRC) patients.

Cytometry by time-of-flight (CyTOF) and RNA-seq was applied to characterise immune cell heterogeneity in a discovery cohort including tumour, blood and intestinal architecture comprising epithelium, lamina propria, submucosa, muscularis propria of normal bowel and tumour-adjacent bowel tissues. Immunoprofiling was also validated by a validation cohort using single-cell RNA sequencing, spatial transcription, CyTOF and multiplex immunofluorescent staining.

Based on cell phenotype and transcription, we identify distinct immunotypes in the CRC macroenvironment including blood, tumour and different intestinal architecture, showing disturbed immune cell compositions, increasing expression of immunosuppressive markers and cell-cell interactions contributing to immunosuppressive regulation. Furthermore, we evaluate immune macroenvironment influencing factors including tertiary lymphoid structures (TLSs), consensus molecular subtypes (CMSs) and immune checkpoint inhibitors (ICIs). TLS presence fuels anti-tumour immunity by promoting CD8+ T cell infiltration and altering activation or suppression of T cell systematically. TLS presence correlates with patient survival, intrinsic CMS and therapeutic efficacy of ICI. PD-1 and CD69 expressed in effector memory CD8+ T cells from blood can predict TLS presence in the CRC macroenvironment, serving as potential biomarkers for stratifying CRC patients into immunotherapy.

Our findings provide insights into the CRC immune macroenvironment, highlighting immune cell suppression and activation in tumourigenesis. Our study illustrates the potential utility of blood for predicting immunotherapy response.

Distinct immunotypes are identified in the CRC macroenvironment. TLS and immunotherapy exert influence on the immune macroenvironment. TLS presence correlates with patient survival, CMS and therapeutic efficacy of ICI. PD-1 and CD69 expressed in CD8+ Tem from blood can predict TLS presence in the CRC macroenvironment.

Antigen-presenting cells (APCs) process tumor vaccines and present tumor antigens as the first signals to T cells to activate anti-tumor immunity, which process requires the assistance of co-stimulatory second signals on APCs. The immune checkpoint programmed death ligand 1 (PD-L1) not only mediates the immune escape of tumor cells but also acts as a co-inhibitory second signal on APCs. The serious dysfunction of second signals due to the high expression of PD-L1 on APCs in the tumor body results in the inefficiency of tumor vaccines. To overcome this challenge, a previously established Plug-and-Display tumor vaccine platform based on bacterial outer membrane vesicles (OMVs) is developed into an "Antigen Presentation Signal Enhancer" (APSE) by surface-modifying PD-L1 antibodies (αPD-L1). While delivering tumor antigens, APSE can activate the expression of co-stimulatory second signals in APCs due to the high immunogenicity of OMVs. More importantly, the surface-modified αPD-L1 binds to the co-inhibitory signals PD-L1, potentially restoring CD80 function and ensuring efficient co-stimulatory second signals and activation of anti-tumor immunity. The results reveal the importance of PD-L1 blockage in the initiation process of anti-tumor immunity, and the second signal modulation capability of APSE can expand the application potential of cancer vaccines to less immunogenic malignancies.

This study aimed to explore the prognostic value of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) metabolic parameters of immune organs and hematological immune-related markers for patients with locally advanced cervical cancer (LACC) undergoing concurrent chemoradiotherapy (CCRT), and to establish prognostic nomograms based on these potential biomarkers.

A total of 180 patients with LACC undergoing CCRT were retrospectively reviewed and randomly divided into training and validation groups at a 7:3 ratio. Cox regression analysis was performed to identify independent prognostic factors for progression-free survival (PFS) and overall survival (OS) from hematological immune-related markers and 18F-FDG PET/CT metabolic parameters of the primary tumor, spleen, and bone marrow (BM). Nomograms were developed and evaluated using receiver operating characteristic curves, concordance index (C-index), calibration curves, and decision curve analysis (DCA). Spearman correlation analysis was used to assess the relationships among metabolic parameters.

Multivariable analysis identified International Federation of Gynecology and Obstetrics (FIGO) stage, neutrophil-to-lymphocyte ratio (NLR), and spleen maximum standardized uptake value (SUVspleen) as independent prognostic factors for PFS. For OS, the independent prognostic factors were FIGO stage, NLR, metabolic tumor volume, and SUVspleen. The nomograms demonstrated better prognostic performance for PFS (area under curve [AUC]: 0.875 and 0.862; C-index: 0.809 and 0.775) and OS (AUC: 0.858 and 0.814; C-index: 0.828 and 0.792) in the training and validation groups. Calibration curves and DCA indicated that the nomograms have good predictive accuracy and clinical utility. Spearman correlation analysis revealed significant positive correlations among total lesion glycolysis, SUVspleen, SUVBM, and platelet-to-lymphocyte ratio.

The nomograms based on metabolic parameters of immune organs and hematological immune-related markers demonstrated high predictive value for patients with LACC undergoing CCRT. The observed correlations between the metabolic parameters of the primary tumor and immune organs suggest a widespread disturbance of systemic immunity caused by the tumor.

Lymph node metastasis is an important biological feature of oral squamous cell carcinoma, bearing poorly prognostic implications. However, the role of lymph node metastasis in cancer progression remains inconclusive. On the one hand, lymph nodes are pivotal sites for initiating specific immunity, which is crucial for maintaining antitumor immune response. On the other hand, they also serve as primary conduits for tumor metastasis, with lymph node colonization potentially inducing systemic immune dysfunction, thereby further promoting tumor progression. Considering this paradoxical role of lymph nodes, comprehending their impact on the primary tumor and immunity becomes paramount. Furthermore, leveraging these distinctive attributes of lymph nodes presents novel avenues for enhancing current therapeutic strategies against oral squamous cell carcinoma. This review summarizes the anatomical and molecular profiles of lymph node metastasis in oral squamous cell carcinoma, elucidating how lymphatic involvement compromises antitumor immunity, thus facilitating primary tumor and distant metastases. Additionally, it explores avenues for harnessing these mechanisms to optimize clinical interventions.

Breast cancer is one of the most prevalent cancers worldwide. Recent studies have increasingly emphasized the role of oxidative stress in the initiation and progression of breast cancer. This article reviews how oxidative stress imbalance influences the occurrence and advancement of breast cancer, elucidating the intricate mechanisms through which reactive oxygen species (ROS) operate in this context and their potential therapeutic applications. By highlighting these critical insights, this review aims to enhance our understanding of oxidative stress as a potential target for innovative therapeutic strategies in the management of breast cancer.

The biology centered around the TGF-β type I receptor activin receptor-like kinase (ALK) 1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than 2 decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant antiangiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+ monocytes into circulation, and their eventual extravasation. Notably, ACVRL1+ TAMs coincided with an immunosuppressive phenotype and were overrepresented in human cancers progressing on therapy. Accordingly, breast cancer patients with a prominent ACVRL1hi TAM signature exhibited a significantly shorter survival. In conclusion, we shed light on an unexpected multimodal regulation of tumorigenic phenotypes by ALK1 and demonstrate its utility as a target for antiangiogenic immunotherapy.

Cancers can avoid immune-mediated elimination by acquiring traits that disrupt antitumour immunity. These mechanisms of immune evasion are selected and reinforced during tumour evolution under immune pressure. Some immunogenic subclones are effectively eliminated by antitumour T cell responses (a process known as immunoediting), which results in a clonally selected tumour. Other cancer cells arise to resist immunoediting, which leads to a tumour that includes several distinct cancer cell populations (referred to as intratumour heterogeneity (ITH)). Tumours with high ITH are associated with poor patient outcomes and a lack of responsiveness to immune checkpoint blockade therapy. In this Review, we discuss the different ways that cancer cells evade the immune system and how these mechanisms impact immunoediting and tumour evolution. We also describe how subclonal antigen presentation in tumours with high ITH can result in immune evasion.

Immunotherapy is regarded as a potent cancer treatment, with DC vaccines playing a crucial role. Although clinical trials have demonstrated the safety and efficacy of DC vaccines, loading antigens in vitro is challenging, and their therapeutic effects remain unpredictable. Moreover, the diverse subtypes and maturity states of DCs in the body could induce both immune responses and immune tolerance, potentially affecting the vaccine's efficacy. Hence, the optimization of DC vaccines remains imperative. Our study discovered a new therapeutic strategy by using CT26 and MC38 mouse colon cancer models, as well as LLC mouse lung cancer models. The strategy involved the synergistic activation of DCs through intertumoral administration of TLR4 agonist high-mobility group nucleosome binding protein 1 (HMGN1) and TLR7/8 agonist (R848/resiquimod), combined with intraperitoneal administration of TNFR2 immunosuppressant antibody. The experimental results indicated that the combined use of HMGN1, R848, and α-TNFR2 had no effect on LLC cold tumors. However, it was effective in eradicating CT26 and MC38 colon cancer and inducing long-term immune memory. The combination of these three drugs altered the TME and promoted an increase in anti-tumor immune components. This may provide a promising new treatment strategy for colon cancer.

Tumorigenesis embodies the formation of a heterotypic tumour microenvironment (TME) that, among its many functions, enables the evasion of T cell-mediated immune responses. Remarkably, most TME cell types, including cancer cells, fibroblasts, myeloid cells, vascular endothelial cells and pericytes, can be stimulated to deploy immunoregulatory programmes. These programmes involve regulatory inducers (signals-in) and functional effectors (signals-out) that impair CD8+ and CD4+ T cell activity through cytokines, growth factors, immune checkpoints and metabolites. Some signals target specific cell types, whereas others, such as transforming growth factor-β (TGFβ) and prostaglandin E2 (PGE2), exert broad, pleiotropic effects; as signals-in, they trigger immunosuppressive programmes in most TME cell types, and as signals-out, they directly inhibit T cells and also modulate other cells to reinforce immunosuppression. This functional diversity and redundancy pose a challenge for therapeutic targeting of the immune-evasive TME. Fundamentally, the commonality of regulatory programmes aimed at abrogating T cell activity, along with paracrine signalling between cells of the TME, suggests that many normal cell types are hard-wired with latent functions that can be triggered to prevent inappropriate immune attack. This intrinsic capability is evidently co-opted throughout the TME, enabling tumours to evade immune destruction.

We aimed to investigate the prognostic significance of tumor size in metastatic renal cell carcinoma (mRCC) by comparing the effectiveness of dual immune checkpoint inhibitor (IOIO) and immune checkpoint inhibitor combined with tyrosine kinase inhibitor (IOTKI) therapies.

This retrospective observational study included patients with mRCC diagnosed between October 2014 and February 2024 who received IOIO or IOTKI treatment at Kobe University Hospital and 5 affiliated hospitals. Clinical and imaging data were collected, and target lesions were measured according to RECIST v.1.1 criteria. Time-dependent ROC curve analysis was performed to evaluate the prognostic value of tumor size, nephrectomy status, and IMDC risk criteria for progression-free survival (PFS) and overall survival (OS).

The study included 180 mRCC patients, consisting of 99 receiving IOIO therapy and 81 receiving IOTKI therapy. Time-dependent AUC analysis showed that tumor size had a higher predictive ability for PFS and OS in the IOIO group than the IOTKI group. In multivariate analysis, tumor size was a significant independent prognostic factor for PFS (HR: 1.010, 95% CI: 1.004-1.016, P < 0.001) in the IOIO group. Moreover, the AUC for tumor size was consistently superior in predicting outcomes compared to nephrectomy status and IMDC risk classification in the IOIO group. Kaplan-Meier curves indicated that tumor size effectively stratified PFS in both nephrectomized and non-nephrectomized cases.

Tumor size significantly impacts the prognosis of mRCC patients treated with IOIO therapy, demonstrating greater predictive ability than nephrectomy status and IMDC risk classification. These findings suggest that tumor volume should be considered a critical factor in treatment decision-making for renal cancer, particularly in patients undergoing IOIO therapy.

Renal cell carcinoma (RCC) was diagnosed in over 400 000 individuals globally in 2020, making it a significant global health concern. The incidence of RCC varies by region and overall mortality rates have been declining. This decline is attributed in part to advancements in early cancer detection through imaging and the development of more effective systemic therapies. Cytoreductive nephrectomy (CN) was adopted as a standard treatment for metastatic RCC (mRCC) based on clinical experience and early clinical trials. However, the treatment landscape has shifted with the introduction of tyrosine kinase inhibitors (TKI) in 2007 and, more recently, immune checkpoint inhibitors (ICIs). Dual ICI therapy and combinations of ICIs with TKIs are collectively referred to as immuno-combination therapies and have become standard first-line treatments. This review examines the evolving role of CN in the era of immuno-combination therapies, with a focus on patient selection and the timing of surgery. The immunogenic nature of RCC, characterized by spontaneous tumor regression and immune cell infiltration, suggests a potential benefit from combining CN with ICI therapy to enhance treatment outcomes. This is supported by several clinical studies that reported improved outcomes; however, these were limited by their retrospective nature. Ongoing clinical trials, such as NORDIC-SUN, PROBE, and SEVURO-CN, are expected to provide critical insights into the role of CN in the ICI era. Their findings will ultimately guide future clinical decision-making and further refine treatment strategies for mRCC.

Reprogramming tryptophan metabolism (TRP) may be able to overcome immunosuppression and restore the immune checkpoint blockade (ICB) response in patients with epithelial ovarian cancer (EOC) resistant to ICB therapy because TRP metabolism is involved in the kynurenine/indole and serotonin pathways of tryptophan metabolism. Herein, employing amitriptyline (AMI), an antagonist of TLR4 and serotonin transporter (SERT), we revealed that AMI remodels the immunological landscape of EOC. In particular, AMI lowered the expression of IDO1, IL-4I1, and PD-L1, the quantity of KYN and indoles, and the level of immunosuppressive immune cells MDSC, Tregs, and CD8+CD39+/PD-1+ T cell. AMI boosted the killing potential of anti-PD-1-directed CD8+T cells and worked in concert with PD-1 inhibitors to suppress tumor growth and to prolong the survival of EOC-bearing mice. This work highlights AMI as an effective regulator of ICB response by manipulating EOC cell TRP metabolism, indicating it could be a potential strategy for improving EOC ICB therapy.

The immune system plays critical roles in the initiation and progression of colorectal cancer (CRC), and the majority of studies have focused on immune perturbations within the tumor microenvironment. In recent years, systemic immunity, which mainly occurs in the periphery, has attracted much attention. In CRC, both the tumor itself and treatments have extensive effects on systemic immunity, characterized by alterations in circulating cytokines and immune cells. In addition, intact systemic immunity is critical for the efficacy of therapies for CRC, especially immunotherapy. Therefore, various strategies aimed at alleviating the detrimental effects of traditional therapies or directly harnessing the components of systemic immunity for CRC treatment have been developed. However, whether these improvements can translate to survival benefits requires further study. This review aims to comprehensively outline the current knowledge of systemic immunity in CRC.

The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to promote T cells with anti-tumor capabilities. Here, we compared mutant neoantigen (neoAg) peptide-based vaccines with ICT in preclinical models. NeoAg vaccines induce the most robust expansion of proliferating and stem-like PD-1+TCF-1+ neoAg-specific CD8 T cells in tumors. Anti-CTLA-4 and/or anti-PD-1 ICT promotes intratumoral TCF-1- neoAg-specific CD8 T cells, although their phenotype depends in part on the specific ICT used. Anti-CTLA-4 also prompts substantial changes to CD4 T cells, including induction of ICOS+Bhlhe40+ T helper 1 (Th1)-like cells. Although neoAg vaccines or ICTs expand iNOS+ macrophages, neoAg vaccines maintain CX3CR1+CD206+ macrophages expressing the TREM2 receptor, unlike ICT, which suppresses them. TREM2 blockade enhances neoAg vaccine efficacy and is associated with fewer CX3CR1+CD206+ macrophages and induction of neoAg-specific CD8 T cells. Our findings highlight different mechanisms underlying neoAg vaccines and different forms of ICT and identify combinatorial therapies to enhance neoAg vaccine efficacy.

Systemic immunity is essential for driving therapeutically induced antitumor immune responses, and the spleen may reflect alterations in systemic immunity. This study aimed to evaluate the predictive value of contrast-enhanced CT-based spleen radiomics for progression-free survival (PFS) in patients with locally advanced cervical cancer (LACC) who underwent definitive chemoradiotherapy (dCRT). Additionally, we investigated the role of spleen radiomics features and changes in spleen volume in assessing systemic immunity.

This retrospective study included 257 patients with LACC who underwent dCRT. The patients were randomly divided into training and validation groups in a 7:3 ratio. Radiomic features were extracted from CT images obtained before and after dCRT. Radiomic scores (Radscore) were calculated using features selected through least absolute shrinkage and selection operator (LASSO) Cox regression. The percentage change in spleen volume was determined from measurements taken before and after treatment. Independent prognostic factors for PFS were identified through multivariate Cox regression analyses. Model performance was evaluated with the receiver operating characteristic (ROC) curve and the C-index. The Radscore cut-off value, determined from the ROC curve, was used to stratify patients into high- and low-risk survival groups. The Wilcoxon test was used to analyze differences in hematological parameters between different survival risk groups and between different spleen volume change groups. Spearman correlation analysis was used to explore the relationship between spleen volume change and hematological parameters.

Independent prognostic factors included FIGO stage, pre-treatment neutrophil-to-lymphocyte ratio (pre-NLR), spleen volume change, and Radscore. The radiomics-combined model demonstrated the best predictive performance for PFS in both the training group (AUC: 0.923, C-index: 0.884) and the validation group (AUC: 0.895, C-index: 0.834). Compared to the low-risk group, the high-risk group had higher pre-NLR (p = 0.0054) and post-NLR (p = 0.038). Additionally, compared to the decreased spleen volume group, the increased spleen volume group had lower post-NLR (p = 0.0059) and post-treatment platelet-to-lymphocyte ratio (p < 0.001).

Spleen radiomics combined with clinical features can effectively predict PFS in patients with LACC after dCRT. Furthermore, spleen radiomics features and changes in spleen volume can reflect alterations in systemic immunity.

Neuroendocrine tumors (NETs) are presented with metastases due to delayed diagnosis. We aimed to identify NET-related biomarkers from peripheral blood. The development and validation of a multi-gene NETseq ensemble classifier using peripheral blood RNA-Seq is reported. RNA-Seq was performed on peripheral blood samples from 178 NET patients and 73 healthy donors. Distinguishing gene features were identified from a learning cohort (59 PRRT-naïve GEP-NET patients and 38 healthy donors). Ensemble classifier combining the output of five machine learning algorithms viz. Random Forest (RF), Extreme Gradient Boosting (XGBOOST), Gradient Boosting Machine (GBM), Support Vector Machine (SVM), and Logistic Regression (LR) were trained and independently validated in the evaluation cohort (n = 106). The response to PRRT was evaluated in the PRRT cohort (n = 46) and the PRRT response monitoring cohort (n = 16). The response to 177Lu-DOTATATE PRRT was assessed using RECIST 1.1 criteria. The Ensemble classifier trained on 61 gene features, distinguished NET from healthy samples with 100% accuracy in the learning cohort. In an evaluation cohort, the classifier achieved 93% sensitivity (95% CI: 87.8%-98.03%) and 91.4% specificity (95% CI: 82.1%-100%) for PRRT-naïve GEP-NETs (AUROC = 95.4%). The classifier returned >87.5% sensitivity across different tumor characteristics and outperformed serum Chromogranin A sensitivity (χ2 = 21.89, p = 4.161e-6). In the PRRT cohort, RECIST 1.1 responders showed significantly lower NETseq prediction scores after 177Lu-DOTATATE PRRT, in comparison to the non-responders. In an independent response monitoring cohort, paired samples (before PRRT and after 2nd or 3rd cycle of PRRT) were analyzed. The NETseq prediction score significantly decreased in partial responders (p = .002) and marginally reduced in stable disease (p = .068). The NETseq ensemble classifier identified PRRT-naïve GEP-NETs with high accuracy (≥92%) and demonstrated a potential role in early treatment response monitoring in the PRRT setting. This blood-based, non-invasive, multi-analyte molecular method could be developed as a valuable adjunct to conventional methods in the detection and treatment response assessment in NET patients.

Victims of explosive events frequently suffer from blast lung injuries. Immune system has been implicated in the pathogenesis of this disease. However, systemic immune responses underlying the progression and recovery of injury repair remain poorly understood. Here, we depict the systemic landscape of immune dysregulation during blast lung injury and uncover immune recovery patterns. Single-cell analyses reveal dramatic changes in neutrophils, macrophages, monocytes, dendritic cells, and eosinophils after a gas explosion, along with early involvement of CD4 T, CD8 T, and Th17 cells. We demonstrate that myeloid cells primarily exert functions during the acute phase, while the spleen serves as an alternative source of granulocytes. Granulopoiesis is initiated in the bone marrow at a later stage during blast lung injury recovery, rather than at the acute stage. These findings contribute to a better understanding of the pathogenesis and provide valuable insights for potential immune interventions in blast lung injury.

Studying the tumor microenvironment and surrounding lymph nodes is the main focus of current immunological research on soft tissue sarcomas (STS). However, due to the restricted opportunity to examine tumor samples, alternative approaches are required to evaluate immune responses in non-surgical patients. Therefore, the purpose of this study was to evaluate the peripheral immune profile of STS patients, characterize patients accordingly and explore the impact of peripheral immunotypes on patient survival. Blood samples were collected from 55 STS patients and age-matched healthy donors (HD) controls. Deep immunophenotyping and gene expression analysis of whole blood was analyzed using multiparametric flow cytometry and real-time RT-qPCR, respectively. Using xMAP technology, proteomic analysis was also carried out on plasma samples. Unsupervised clustering analysis was used to classify patients based on their immune profiles to further analyze the impact of peripheral immunotypes on patient survival. Significant differences were found between STS patients and HD controls. It was found a contraction of B cells and CD4 T cells compartment, along with decreased expression levels of ICOSLG and CD40LG; a major contribution of suppressor factors, as increased frequency of M-MDSC and memory Tregs, increased expression levels of ARG1, and increased plasma levels of IL-10, soluble VISTA and soluble TIMD-4; and a compromised cytotoxic potential associated with NK and CD8 T cells, namely decreased frequency of CD56dim NK cells, and decreased levels of PRF1, GZMB, and KLRK1. In addition, the patients were classified into three peripheral immunotype groups: "immune-high," "immune-intermediate," and "immune-low." Furthermore, it was found a correlation between these immunotypes and patient survival. Patients classified as "immune-high" exhibited higher levels of immune-related factors linked to cytotoxic/effector activity and longer survival times, whereas patients classified as "immune-low" displayed higher levels of immune factors associated with immunosuppression and shorter survival times. In conclusion, it can be suggested that STS patients have a compromised systemic immunity, and the correlation between immunotypes and survival emphasizes the importance of studying peripheral blood samples in STS. Assessing the peripheral immune response holds promise as a useful method for monitoring and forecasting outcomes in STS.

Rationale: While immunotherapy shows great promise in patients with triple negative breast cancer, many will not respond to treatment. Radiotherapy has the potential to prime the tumor-immune microenvironment for immunotherapy. However, predicting response is difficult due to tumor heterogeneity across patients, which necessitates personalized medicine strategies that incorporate tumor tracking into the therapeutic approach. Here, we investigated the use of ultrasound (US) imaging of the tumor vasculature to monitor the tumor response to treatment. Methods: We utilized ultrafast power doppler US to track the vascular response to radiotherapy over time. We used 4T1 (metastatic) and 67NR (non-metastatic) breast cancer models to determine if US measurements corroborate conventional immunostaining analysis of the tumor vasculature. To evaluate the effects of radiation, tumor volume and vascular index were calculated using US, and the correlation between vascular changes and immune cell infiltration was determined. Results: US tumor measurements and the quantified vascular response to radiation were confirmed with caliper measurements and immunostaining, respectively, demonstrating a proof-of-principle method for non-invasive vascular monitoring. Additionally, we found significant infiltration of CD8+ T cells into irradiated tumors 10 days after radiation, which followed a sustained decline in vascular index and an increase in splenic CD8+ T cells that was first observed 1 day post-radiation. Conclusions: Our findings reveal that ultrafast power doppler US can evaluate changes in tumor vasculature that are indicative of shifts in the tumor-immune microenvironment. This work may lead to improved patient outcomes through observing and predicting response to therapy.

Tumor-reactive T cells play a crucial role in anti-tumor responses, but T cells induced by DNA vaccination are time-consuming processes and exhibit limited anti-tumor efficacy. Therefore, we evaluated the anti-tumor effectiveness of reactive T cells elicited by electroporation (EP)-mediated DNA vaccine targeting epidermal growth factor receptor variant III (pEGFRvIII plasmid), in conjunction with adoptive cell therapy (ACT), involving the transfer of lymphocytes from a pEGFRvIII EP-vaccinated healthy donor.

The validation of the established pEGFRvIII plasmid and EGFRvIII-positive cell model was confirmed through immunofluorescence and western blot analysis. Flow cytometry and cytotoxicity assays were performed to evaluate the functionality of antigen-specific reactive T cells induced by EP-mediated pEGFRvIII vaccines, ACT, or their combination. The anti-tumor effectiveness of EP-mediated pEGFRvIII vaccines alone or combined with ACT was evaluated in the B16F10-EGFRvIII tumor model.

EP-mediated pEGFRvIII vaccines elicited serum antibodies and a robust cellular immune response in both healthy and tumor-bearing mice. However, this response only marginally inhibited early-stage tumor growth in established tumor models. EP-mediated pEGFRvIII vaccination followed by adoptive transfer of lymphocytes from vaccinated healthy donors led to notable anti-tumor efficacy, attributed to the synergistic action of antigen-specific CD4+ Th1 cells supplemented by ACT and antigen-specific CD8+ T cells elicited by the EP-mediated DNA vaccination.

Our preclinical studies results demonstrate an enhanced anti-tumor efficacy of EP-mediated DNA vaccination boosted with adoptively transferred, vaccinated healthy donor-derived allogeneic lymphocytes.

Melanoma is the deadliest form of skin cancer in the United States, with its incidence rates rising in older populations. As the immune system undergoes age-related changes, these alterations can significantly influence tumor progression and the effectiveness of cancer treatments. Recent advancements in understanding immune checkpoint molecules have paved the way for the development of innovative immunotherapies targeting solid tumors. However, the aging tumor microenvironment can play a crucial role in modulating the response to these immunotherapeutic approaches. This review seeks to examine the intricate relationship between age-related changes in the immune system and their impact on the efficacy of immunotherapies, particularly in the context of melanoma. By exploring this complex interplay, we hope to elucidate potential strategies to optimize treatment outcomes for older patients with melanoma, and draw parallels to other cancers.

Amivantamab is an FDA-approved bispecific antibody targeting EGF and Met receptors, with clinical activity against EGFR mutant non-small cell lung cancer (NSCLC). Amivantamab efficacy has been demonstrated to be linked to three mechanisms of action (MOA): immune cell-mediated killing, receptor internalization and degradation, and inhibition of ligand binding to both EGFR and Met receptors. Among the EGFR ligands, we demonstrated that amphiregulin (AREG) is highly expressed in wild-type (WT) EGFR (EGFRWT) NSCLC primary tumors, with significantly higher circulating protein levels in NSCLC patients than in healthy volunteers. Treatment of AREG-stimulated EGFRWT cells/tumors with amivantamab or with an AREG-targeting antibody inhibited ligand-induced signaling and cell/tumor proliferation/growth. Across 11 EGFRWT NSCLC patient-derived xenograft models, amivantamab efficacy correlated with AREG RNA levels. Interestingly, in these models, amivantamab anti-tumor activity was independent of Fc engagement with immune cells, suggesting that, in this context, the ligand-blocking function is sufficient for amivantamab maximal efficacy. Finally, we demonstrated that in lung adenocarcinoma patients, high expression of AREG and EGFR mutations were mutually exclusive. In conclusion, these data 1) highlight EGFR ligand AREG as a driver of tumor growth in some EGFRWT NSCLC models, 2) illustrate the preclinical efficacy of amivantamab in ligand-driven EGFRWT NSCLC, and 3) identify AREG as a potential predictive biomarker for amivantamab activity in EGFRWT NSCLC.

Immunotherapy has profoundly changed the treatment of gastric cancer, but only a minority of patients benefit from immunotherapy. Therefore, numerous studies have been devoted to clarifying the mechanisms underlying resistance to immunotherapy or developing biomarkers for patient stratification. However, previous studies have focused mainly on the tumor microenvironment. Systemic immune perturbations have long been observed in patients with gastric cancer, and the involvement of the peripheral immune system in effective anticancer responses has attracted much attention in recent years. Therefore, understanding the distinct types of systemic immune organization in gastric cancer will aid personalized treatment designed to pair with traditional therapies to alleviate their detrimental effects on systemic immunity or to directly activate the anticancer response of systemic immunity. Herein, this review aims to comprehensively summarize systemic immunity in gastric cancer, including perturbations in systemic immunity induced by cancer and traditional therapies, and the potential clinical applications of systemic immunity in the detection, prediction, prognosis and therapy of gastric cancer.

Breast cancer cells suppress the host immune system to efficiently invade the lymph nodes; however, the underlying mechanism remains incompletely understood. Here, we aimed to comprehensively characterise the effects of breast cancers on immune cells in the lymph nodes.

We collected non-metastatic and metastatic lymph node samples from 6 patients with breast cancer with lymph node metastasis. We performed bulk transcriptomics, spatial transcriptomics, and imaging mass cytometry to analyse the obtained lymph nodes. Furthermore, we conducted histological analyses against a larger patient cohort (474 slices from 58 patients).

The comparison between paired lymph nodes with and without metastasis from the same patients demonstrated that the number of CD169+ lymph node sinus macrophages, an initiator of anti-cancer immunity, was reduced in metastatic lymph nodes (36.7 ± 21.1 vs 7.3 ± 7.0 cells/mm2, p = 0.0087), whereas the numbers of other major immune cell types were unaltered. We also detected that the infiltration of CD169+ macrophages into metastasised cancer tissues differed by section location within tumours, suggesting that CD169+ macrophages were gradually decreased after anti-cancer reactions. Furthermore, CD169+ macrophage elimination was prevalent in major breast cancer subtypes and correlated with breast cancer staging (p = 0.022).

We concluded that lymph nodes with breast cancer metastases have fewer CD169+ macrophages, which may be detrimental to the activity of anti-cancer immunity.

JSPS KAKENHI (16H06279, 20H03451, 20H04842, 22H04925, 19K16770, and 21K15530, 24K02236), JSPS Fellows (JP22KJ1822), AMED (JP21ck0106698), JST FOREST (JPMJFR2062), Caravel, Co., Ltd, Japan Foundation for Applied Enzymology, and Sumitomo Pharma Co., Ltd. under SKIPS.

Immuno-stimulative effect of chemotherapy (ISECT) is recognized as a potential alternative to conventional immunotherapies, however, the clinical application is constrained by its inefficiency. Metronomic chemotherapy, though designed to overcome these limitations, offers inconsistent results, with effectiveness varying based on cancer types, stages, and patient-specific factors. In parallel, a wealth of preclinical nanomaterials holds considerable promise for ISECT improvement by modulating the cancer-immunity cycle. In the area of biomedical nanomaterials, current literature reviews mainly concentrate on a specific category of nanomaterials and nanotechnological perspectives, while two essential issues are still lacking, i.e., a comprehensive analysis addressing the causes for ISECT inefficiency and a thorough summary elaborating the nanomaterials for ISECT improvement. This review thus aims to fill these gaps and catalyze further development in this field. For the first time, this review comprehensively discusses the causes of ISECT inefficiency. It then meticulously categorizes six types of nanomaterials for improving ISECT. Subsequently, practical strategies are further proposed for addressing inefficient ISECT, along with a detailed discussion on exemplary nanomedicines. Finally, this review provides insights into the challenges and perspectives for improving chemo-immunotherapy by innovations in nanomaterials.

The growth and metastasis of pancreatic cancer (PC) has been found to be closely associated with liquid-liquid phase separation (LLPS). This study sought to identify LLPS-related biomarkers in PC to construct a robust prognostic model.

Transcriptomic data and clinical information related to PC were retrieved from publicly accessible databases. The PC-related data set was subjected to differential expression, Mendelian randomization (MR), univariate Cox, and least absolute selection and shrinkage operator analyses to identify biomarkers. Using the biomarkers, we subsequently constructed a risk model, identified the independent prognostic factors of PC, established a nomogram, and conducted an immune analysis.

The study identified four genes linked with an increased risk of PC; that is, PYGB, ACTR3, CCNA2, and ITGB1. Conversely, ATP8A1, and RAP1GAP2 were found to provide protection against PC. These findings contributed significantly to the development of a highly precise risk model in which risk, age, and pathology N stage were categorized as independent factors in predicting the prognosis of PC patients. Using these factors, a nomogram was established to predict survival outcomes accurately. An immune analysis revealed varying levels of eosinophils, gamma delta T cells, and other immune cells between the distinct risk groups. The high-risk patients exhibited increased potential for immune escape, while the low-risk patients showed a higher response to immunotherapy.

Six genes were identified as having potential causal relationships with PC. These genes were integrated into a prognostic risk model, thereby serving as unique prognostic signatures. Our findings provide novel insights into predicting the prognosis of PC patients.

Early detection can significantly reduce mortality due to lung cancer. Presented here is an approach for developing a blood-based screening panel based on clonal hematopoietic mutations. Animal model studies suggest that clonal hematopoietic mutations in tumor infiltrating immune cells can modulate cancer progression, representing potential predictive biomarkers. The goal of this study was to determine if the clonal expansion of these mutations in blood samples could predict the occurrence of lung cancer. A set of 98 potentially pathogenic clonal hematopoietic mutations in tumor infiltrating immune cells were identified using sequencing data from lung cancer samples. These mutations were used as predictors to develop a logistic regression machine learning model. The model was tested on sequencing data from a separate set of 578 lung cancer and 545 non-cancer samples from 18 different cohorts. The logistic regression model correctly classified lung cancer and non-cancer blood samples with 94.12% sensitivity (95% Confidence Interval: 92.20-96.04%) and 85.96% specificity (95% Confidence Interval: 82.98-88.95%). Our results suggest that it may be possible to develop an accurate blood-based lung cancer screening panel using this approach. Unlike most other "liquid biopsies" currently under development, the approach presented here is based on standard sequencing protocols and uses a relatively small number of rationally selected mutations as predictors.

Distant metastasis, the leading cause of cancer death, is efficiently kept in check by immune surveillance. Studies have uncovered peripheral natural killer (NK) cells as key antimetastatic effectors and their dysregulation during metastasis. However, the molecular mechanism governing NK cell dysfunction links to metastasis remains elusive. Herein, MAP4K1 encoding HPK1 is aberrantly overexpressed in dysfunctional NK cells in the periphery and the metastatic site. Conditional HPK1 overexpression in NK cells suffices to exacerbate melanoma lung metastasis but not primary tumor growth. Conversely, MAP4K1-deficient mice are resistant to metastasis and further protected by combined immune-checkpoint inhibitors. Mechanistically, HPK1 restrains NK cell cytotoxicity and expansion via activating receptors. Likewise, HPK1 limits human NK cell activation and associates with melanoma NK cell dysfunction couples to TGF-β1 and patient response to immune checkpoint therapy. Thus, HPK1 is an intracellular checkpoint controlling NK-target cell responses, which is dysregulated and hijacked by tumors during metastatic progression.

Cancer is a major cause of global mortality, both in affluent countries and increasingly in developing nations. Many patients with cancer experience reduced life expectancy and have metastatic disease at the time of death. However, the more precise causes of mortality and patient deterioration before death remain poorly understood. This scarcity of information, particularly the lack of mechanistic insights, presents a challenge for the development of novel treatment strategies to improve the quality of, and potentially extend, life for patients with late-stage cancer. In addition, earlier deployment of existing strategies to prolong quality of life is highly desirable. In this Roadmap, we review the proximal causes of mortality in patients with cancer and discuss current knowledge about the interconnections between mechanisms that contribute to mortality, before finally proposing new and improved avenues for data collection, research and the development of treatment strategies that may improve quality of life for patients.