[Characteristics of the tumor microenvironment and therapeutic progress in malignant pleural effusion].

Malignant pleural effusion (MPE) can be secondary to various advanced malignant tumors. Although systemic anti tumor therapy may be effective in primary tumors, it cannot reduce the accumulation of MPE in proportion of the patients. The interaction of tumor cells, immune cells, and mesenchymal cells, as well as the abnormal proliferation of tumor-associated blood vessels, together create an immunosuppressive microenvironment for MPE, which promotes the abnormal proliferation of tumor cells and the accumulation of MPE. With the in-depth study of the tumor microenvironment, the application of local systemic anti-tumor therapy with local intrathoracic application of immune checkpoint inhibitors, immune cells, cytokines, and gene-mediated cytotoxic immunotherapy are able to alleviate the immunosuppressive tumor microenvironment and inhibit the accumulation of MPE. This article aimed to describe the tumor microenvironment in MPE and provide clues for identifying novel therapeutic targets.

[Effect of glucocorticoids on the efficacy of non-small cell lung cancer patients treated with immune-checkpoint inhibitors].

Lung cancer is a highly lethal malignant tumor worldwide and in China, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases globally. In recent years, immune checkpoint inhibitor (ICI) had changed the paradigm of lung cancer treatment, either alone or in combination with chemotherapy and recomended as the first-line treatment for NSCLC. NSCLC patients often required glucocorticoid(GC) due to the cancer itself, tumor complications, or immune-related adverse event (irAE). GC had sparked debates on their impact on the therapeutic effectiveness of ICI in NSCLC patients as a substance with immunomodulatory effects. While some studies suggested that GC use did not influence patients survival, others argued the opposite. Understanding the effects of GC on immunotherapy is crucial for managing complaications in cancer patients and addressing irAE. This review explores the impact of GC on the efficacy of ICI in NSCLC patients, aiming to provide insights for clinical treatment.

Novel mRNA adjuvant ImmunER enhances prostate cancer tumor-associated antigen mRNA therapy via augmenting T cell activity.

Prostate cancer (PCa) is characterized as a "cold tumor" with limited immune responses, rendering the tumor resistant to immune checkpoint inhibitors (ICI). Therapeutic messenger RNA (mRNA) vaccines have emerged as a promising strategy to overcome this challenge by enhancing immune reactivity and significantly boosting anti-tumor efficacy. In our study, we synthesized Tetra, an mRNA vaccine mixed with multiple tumor-associated antigens, and ImmunER, an immune-enhancing adjuvant, aiming to induce potent anti-tumor immunity. ImmunER exhibited the capacity to promote dendritic cells (DCs) maturation, enhance DCs migration, and improve antigen presentation at both cellular and animal levels. Moreover, Tetra, in combination with ImmunER, induced a transformation of bone marrow-derived dendritic cells (BMDCs) to cDC1-CCL22 and up-regulated the JAK-STAT1 pathway, promoting the release of IL-12, TNF-α, and other cytokines. This cascade led to enhanced proliferation and activation of T cells, resulting in effective killing of tumor cells. In vivo experiments further revealed that Tetra + ImmunER increased CD8+T cell infiltration and activation in RM-1-PSMA tumor tissues. In summary, our findings underscore the promising potential of the integrated Tetra and ImmunER mRNA-LNP therapy for robust anti-tumor immunity in PCa.

PET/CT in the Evaluation of CAR-T Cell Immunotherapy in Hematological Malignancies.

Chimeric antigen receptor (CAR)-T cell-based immunotherapy has emerged as a path-breaking strategy for certain hematological malignancies. Assessment of the response to CAR-T therapy using quantitative imaging techniques such as positron emission tomography/computed tomography (PET/CT) has been broadly investigated. However, the definitive role of PET/CT in CAR-T therapy remains to be established. [18F]FDG PET/CT has demonstrated high sensitivity and specificity for differentiating patients with a partial and complete response after CAR-T therapy in lymphoma. The early therapeutic response and immune-related adverse effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome can also be detected on [18F]FDG PET images. In otherwise asymptomatic lymphoma patients with partial response following CAR-T therapy, the only positive findings could be abnormal PET/CT results. In multiple myeloma, a negative [18F]FDG PET/CT after receiving B-cell maturation antigen-directed CAR-T therapy has been associated with a favorable prognosis. In leukemia, [18F]FDG PET/CT can detect extramedullary metastases and treatment responses after therapy. Hence, PET/CT is a valuable imaging tool for patients undergoing CAR-T therapy for pretreatment evaluation, monitoring treatment response, assessing safety, and guiding therapeutic strategies. Developing guidelines with standardized cutoff values for various PET parameters and tumor cell-specific tracers may improve the efficacy and safety of CAR-T therapy.

CD161+CD127+CD8+ T cell subsets can predict the efficacy of anti-PD-1 immunotherapy in non-small cell lung cancer with diabetes mellitus.

The role of CD161+CD127+CD8+ T cells in non-small cell lung cancer (NSCLC) patients with diabetes remains unexplored. This study determined the prevalence, phenotype, and function of CD8+ T cell subsets in NSCLC with diabetes. We recruited NSCLC patients (n = 436) treated with anti-PD-1 immunotherapy as first-line treatment. The progression-free survival (PFS), overall survival (OS), T cells infiltration, and peripheral blood immunological characteristics were analyzed in NSCLC patients with or without diabetes. NSCLC patients with diabetes exhibited shorter PFS and OS (p = 0.0069 and p = 0.012, respectively) and significantly lower CD8+ T cells infiltration. Mass cytometry by time-of-flight (CyTOF) showed a higher percentage of CD161+CD127+CD8+ T cells among CD8+T cells in NSCLC with diabetes before anti-PD-1 treatment (p = 0.0071) than that in NSCLC without diabetes and this trend continued after anti-PD-1 treatment (p = 0.0393). Flow cytometry and multiple-immunofluorescence confirmed that NSCLC with diabetes had significantly higher CD161+CD127+CD8+ T cells to CD8+T cells ratios than NSCLC patients without diabetes. The RNA-sequencing analysis revealed immune-cytotoxic genes were reduced in the CD161+CD127+CD8+ T cell subset compared to CD161+CD127-CD8+ T cells in NSCLC with diabetes. CD161+CD127+CD8+ T cells exhibited more T cell-exhausted phenotypes in NSCLC with diabetes. NSCLC patients with diabetes with ≥ 6.3% CD161+CD127+CD8+ T cells to CD8+T cells ratios showed worse PFS. These findings indicate that diabetes is a risk factor for NSCLC patients who undergo anti-PD-1 immunotherapy.CD161+CD127+CD8+ T cells could be a key indicator of a poor prognosis in NSCLC with diabetes. Our findings would help in advancing anti-PD-1 therapy in NSCLC patients with diabetes.

Improving cancer immunotherapy in prostate cancer by modulating T cell function through targeting the galectin-1.

Our study aimed to elucidate the role of Galectin-1 (Gal-1) role in the immunosuppressive tumor microenvironment (TME) of prostate cancer (PCa). Our previous findings demonstrated a correlation between elevated Gal-1 expression and advanced PCa stages. In this study, we also observed that Gal-1 is expressed around the tumor stroma and its expression level is associated with PCa progression. We identified that Gal-1 could be secreted by PCa cells, and secreted Gal-1 has the potential to induce T cell apoptosis. Gal-1 knockdown or inhibition of Gal-1 function by LLS30 suppresses T cell apoptosis resulting in increased intratumoral T cell infiltration. Importantly, LLS30 treatment significantly improved the antitumor efficacy of anti-PD-1 in vivo. Mechanistically, LLS30 binds to the carbohydrate recognition domain (CRD) of Gal-1, disrupting its binding to CD45 leading to the suppression of T cell apoptosis. In addition, RNA-seq analysis revealed a novel mechanism of action for LLS30, linking its tumor-intrinsic oncogenic effects to anti-tumor immunity. These findings suggested that tumor-derived Gal-1 contributes to the immunosuppressive TME in PCa by inducing apoptosis in effector T cells. Targeting Gal-1 with LLS30 may offer a strategy to enhance anti-tumor immunity and improve immunotherapy.

Multi-omics analysis and experimental validation of the value of monocyte-associated features in prostate cancer prognosis and immunotherapy.

Background: Monocytes play a critical role in tumor initiation and progression, with their impact on prostate adenocarcinoma (PRAD) not yet fully understood. This study aimed to identify key monocyte-related genes and elucidate their mechanisms in PRAD. Method: Utilizing the TCGA-PRAD dataset, immune cell infiltration levels were assessed using CIBERSORT, and their correlation with patient prognosis was analyzed. The WGCNA method pinpointed 14 crucial monocyte-related genes. A diagnostic model focused on monocytes was developed using a combination of machine learning algorithms, while a prognostic model was created using the LASSO algorithm, both of which were validated. Random forest and gradient boosting machine singled out CCNA2 as the most significant gene related to prognosis in monocytes, with its function further investigated through gene enrichment analysis. Mendelian randomization analysis of the association of HLA-DR high-expressing monocytes with PRAD. Molecular docking was employed to assess the binding affinity of CCNA2 with targeted drugs for PRAD, and experimental validation confirmed the expression and prognostic value of CCNA2 in PRAD. Result: Based on the identification of 14 monocyte-related genes by WGCNA, we developed a diagnostic model for PRAD using a combination of multiple machine learning algorithms. Additionally, we constructed a prognostic model using the LASSO algorithm, both of which demonstrated excellent predictive capabilities. Analysis with random forest and gradient boosting machine algorithms further supported the potential prognostic value of CCNA2 in PRAD. Gene enrichment analysis revealed the association of CCNA2 with the regulation of cell cycle and cellular senescence in PRAD. Mendelian randomization analysis confirmed that monocytes expressing high levels of HLA-DR may promote PRAD. Molecular docking results suggested a strong affinity of CCNA2 for drugs targeting PRAD. Furthermore, immunohistochemistry experiments validated the upregulation of CCNA2 expression in PRAD and its correlation with patient prognosis. Conclusion: Our findings offer new insights into monocyte heterogeneity and its role in PRAD. Furthermore, CCNA2 holds potential as a novel targeted drug for PRAD.

Dual immunotherapy alternating with anti-PD-1 antibody plus liposomal doxorubicin show good efficacy in prostate epithelioid hemangioendothelioma: a case report.

Epithelioid hemangioendothelioma is a rare vascular malignancy, and currently, there is no standard treatment regimen for this disease and existing treatment options have limited efficacy. In this case report, we present a patient with lung and lymph node metastases from prostate epithelioid hemangioendothelioma who achieved a significant partial response. This was accomplished through alternating nivolumab therapy with ipilimumab and liposomal doxorubicin, resulting in a progression-free-survival more than 6 months to date. The treatment was well-tolerated throughout. Our report suggests that dual immunotherapy alternating with anti-PD-1antibody plus doxorubicin may be a potential treatment modality for epithelioid hemangioendothelioma. However, larger sample studies are necessary to ascertain the effectiveness of this treatment strategy and it is essential to continue monitoring this patient to sustain progression-free survival and overall survival.

Unlocking the potential of pyroptosis in tumor immunotherapy: a new horizon in cancer treatment.

Background: The interaction between pyroptosis-a form of programmed cell death-and tumor immunity represents a burgeoning field of interest. Pyroptosis exhibits a dual role in cancer: it can both promote tumor development and counteract it by activating immune responses that inhibit tumor evasion and encourage cell death. Current tumor immunotherapy strategies, notably CAR-T cell therapy and immune checkpoint inhibitors (ICIs), alongside the potential of certain traditional Chinese medicinal compounds, highlight the intricate relationship between pyroptosis and cancer immunity. As research delves deeper into pyroptosis mechanisms within tumor therapy, its application in enhancing tumor immune responses emerges as a novel research avenue. Purpose: This review aims to elucidate the mechanisms underlying pyroptosis, its impact on tumor biology, and the advancements in tumor immunotherapy research. Methods: A comprehensive literature review was conducted across PubMed, Embase, CNKI, and Wanfang Database from the inception of the study until August 22, 2023. The search employed keywords such as "pyroptosis", "cancer", "tumor", "mechanism", "immunity", "gasdermin", "ICB", "CAR-T", "PD-1", "PD-L1", "herbal medicine", "botanical medicine", "Chinese medicine", "traditional Chinese medicine", "immunotherapy", linked by AND/OR, to capture the latest findings in pyroptosis and tumor immunotherapy. Results: Pyroptosis is governed by a complex mechanism, with the Gasdermin family playing a pivotal role. While promising for tumor immunotherapy application, research into pyroptosis's effect on tumor immunity is still evolving. Notably, certain traditional Chinese medicine ingredients have been identified as potential pyroptosis inducers, meriting further exploration. Conclusion: This review consolidates current knowledge on pyroptosis's role in tumor immunotherapy. It reveals pyroptosis as a beneficial factor in the immunotherapeutic landscape, suggesting that leveraging pyroptosis for developing novel cancer treatment strategies, including those involving traditional Chinese medicine, represents a forward-looking approach in oncology.

A machine learning radiomics based on enhanced computed tomography to predict neoadjuvant immunotherapy for resectable esophageal squamous cell carcinoma.

Background: Patients with resectable esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunotherapy (NIT) display variable treatment responses. The purpose of this study is to establish and validate a radiomics based on enhanced computed tomography (CT) and combined with clinical data to predict the major pathological response to NIT in ESCC patients. Methods: This retrospective study included 82 ESCC patients who were randomly divided into the training group (n = 57) and the validation group (n = 25). Radiomic features were derived from the tumor region in enhanced CT images obtained before treatment. After feature reduction and screening, radiomics was established. Logistic regression analysis was conducted to select clinical variables. The predictive model integrating radiomics and clinical data was constructed and presented as a nomogram. Area under curve (AUC) was applied to evaluate the predictive ability of the models, and decision curve analysis (DCA) and calibration curves were performed to test the application of the models. Results: One clinical data (radiotherapy) and 10 radiomic features were identified and applied for the predictive model. The radiomics integrated with clinical data could achieve excellent predictive performance, with AUC values of 0.93 (95% CI 0.87-0.99) and 0.85 (95% CI 0.69-1.00) in the training group and the validation group, respectively. DCA and calibration curves demonstrated a good clinical feasibility and utility of this model. Conclusion: Enhanced CT image-based radiomics could predict the response of ESCC patients to NIT with high accuracy and robustness. The developed predictive model offers a valuable tool for assessing treatment efficacy prior to initiating therapy, thus providing individualized treatment regimens for patients.

Nasal tau immunotherapy clears intracellular tau pathology and improves cognitive functions in aged tauopathy mice.

Pathological tau aggregates cause cognitive decline in neurodegenerative tauopathies, including Alzheimer's disease (AD). These aggregates are prevalent within intracellular compartments. Current tau immunotherapies have shown limited efficacy in clearing intracellular tau aggregates and improving cognition in clinical trials. In this study, we developed toxic tau conformation-specific monoclonal antibody-2 (TTCM2), which selectively recognized pathological tau aggregates in brain tissues from patients with AD, dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP). TTCM2 potently inhibited tau-seeding activity, an essential mechanism underlying tauopathy progression. To effectively target intracellular tau aggregates and ensure rapid delivery to the brain, TTCM2 was loaded in micelles (TTCM2-ms) and administered through the intranasal route. We found that intranasally administered TTCM2-ms efficiently entered the brain in hTau-tauopathy mice, targeting pathological tau in intracellular compartments. Moreover, a single intranasal dose of TTCM2-ms effectively cleared pathological tau, elevated synaptic proteins, and improved cognitive functions in aged tauopathy mice. Mechanistic studies revealed that TTCM2-ms cleared intracellular, synaptic, and seed-competent tau aggregates through tripartite motif-containing 21 (TRIM21), an intracellular antibody receptor and E3 ubiquitin ligase known to facilitate proteasomal degradation of cytosolic antibody-bound proteins. TRIM21 was found to be essential for TTCM2-ms-mediated clearance of tau pathology. Our study collectively provides evidence of the effectiveness of nasal tau immunotherapy in targeting and clearing intracellular tau pathology through TRIM21 and enhancing cognition in aged tauopathy mice. This study could be valuable in designing effective tau immunotherapies for AD and other tauopathies.

[Novel therapies for multiple myeloma].

B-cell maturation antigen (BCMA)-targeting therapy is the most common approach to immunotherapy and cellular therapy for multiple myeloma (MM). Three major agents, CAR-T cells, bispecific antibodies, and ADC have been developed as novel therapeutic agents. CAR-T therapy showed favorable efficacy in the treatment of relapsed and refractory MM (RR MM) and was tried in early lines of therapy. Similarly, bispecific antibodies targeting BCMA or other targets have also shown promising effects in treatment of RR MM, and have been now tested in combination with other agents. Although issues such as poor fitness or exhaustion of T cells and increased susceptibility to viral infection remain to be fully resolved, novel immunotherapies and cellular therapies should further improve the prognosis of patients with RR MM.

Insights into treatment-specific prognostic somatic mutations in NSCLC from the AACR NSCLC GENIE BPC cohort analysis.

BACKGROUND: Treatment of non-small lung cancer (NSCLC) has evolved in recent years, benefiting from advances in immunotherapy and targeted therapy. However, limited biomarkers exist to assist clinicians and patients in selecting the most effective, personalized treatment strategies. Targeted next-generation sequencing-based genomic profiling has become routine in cancer treatment and generated crucial clinicogenomic data over the last decade. This has made the development of mutational biomarkers for drug response possible. METHODS: To investigate the association between a patient's responses to a specific somatic mutation treatment, we analyzed the NSCLC GENIE BPC cohort, which includes 2,004 tumor samples from 1,846 patients. RESULTS: We identified somatic mutation signatures associated with response to immunotherapy and chemotherapy, including carboplatin-, cisplatin-, pemetrexed- or docetaxel-based chemotherapy. The prediction power of the chemotherapy-associated signature was significantly affected by epidermal growth factor receptor (EGFR) mutation status. Therefore, we developed an EGFR wild-type-specific mutation signature for chemotherapy selection. CONCLUSION: Our treatment-specific gene signatures will assist clinicians and patients in selecting from multiple treatment options.

Targeting cytotoxic lymphocyte antigen 4 (CTLA-4) in breast cancer.

Breast cancer (BC) has a high mortality rate and is one of the most common malignancies in the world. Initially, BC was considered non-immunogenic, but a paradigm shift occurred with the discovery of tumor-infiltrating lymphocytes (TILs) and regulatory T cells (Tregs) in the BC tumor microenvironment. CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) immunotherapy has emerged as a treatment option for BC, but it has limitations, including suboptimal antitumor effects and toxicity. Research has demonstrated that anti-CTLA-4 combination therapies, such as Treg depletion, cancer vaccines, and modulation of the gut microbiome, are significantly more effective than CTLA-4 monoclonal antibody (mAB) monotherapy. Second-generation CTLA-4 antibodies are currently being developed to mitigate immune-related adverse events (irAEs) and augment antitumor efficacy. This review examines anti-CTLA-4 mAB in BC, both as monotherapy and in combination with other treatments, and sheds light on ongoing clinical trials, novel CTLA-4 therapeutic strategies, and potential utility of biomarkers in BC.

Immunotherapy for non-small cell lung cancer in the elderly population: a generic protocol.

OBJECTIVES: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the effectiveness and safety of immune checkpoint inhibitors (ICI) as monotherapy or in combination compared to standard of care for elderly people (≥ 65 years) with non-small cell lung cancer (NSCLC).

Advancing lung adenocarcinoma prognosis and immunotherapy prediction with a multi-omics consensus machine learning approach.

Lung adenocarcinoma (LUAD) is a tumour characterized by high tumour heterogeneity. Although there are numerous prognostic and immunotherapeutic options available for LUAD, there is a dearth of precise, individualized treatment plans. We integrated mRNA, lncRNA, microRNA, methylation and mutation data from the TCGA database for LUAD. Utilizing ten clustering algorithms, we identified stable multi-omics consensus clusters (MOCs). These data were then amalgamated with ten machine learning approaches to develop a robust model capable of reliably identifying patient prognosis and predicting immunotherapy outcomes. Through ten clustering algorithms, two prognostically relevant MOCs were identified, with MOC2 showing more favourable outcomes. We subsequently constructed a MOCs-associated machine learning model (MOCM) based on eight MOCs-specific hub genes. Patients characterized by a lower MOCM score exhibited better overall survival and responses to immunotherapy. These findings were consistent across multiple datasets, and compared to many previously published LUAD biomarkers, our MOCM score demonstrated superior predictive performance. Notably, the low MOCM group was more inclined towards 'hot' tumours, characterized by higher levels of immune cell infiltration. Intriguingly, a significant positive correlation between GJB3 and the MOCM score (R = 0.77, p < 0.01) was discovered. Further experiments confirmed that GJB3 significantly enhances LUAD proliferation, invasion and migration, indicating its potential as a key target for LUAD treatment. Our developed MOCM score accurately predicts the prognosis of LUAD patients and identifies potential beneficiaries of immunotherapy, offering broad clinical applicability.

Integrating machine learning and single-cell analysis to uncover lung adenocarcinoma progression and prognostic biomarkers.

The progression of lung adenocarcinoma (LUAD) from atypical adenomatous hyperplasia (AAH) to invasive adenocarcinoma (IAC) involves a complex evolution of tumour cell clusters, the mechanisms of which remain largely unknown. By integrating single-cell datasets and using inferCNV, we identified and analysed tumour cell clusters to explore their heterogeneity and changes in abundance throughout LUAD progression. We applied gene set variation analysis (GSVA), pseudotime analysis, scMetabolism, and Cytotrace scores to study biological functions, metabolic profiles and stemness traits. A predictive model for prognosis, based on key cluster marker genes, was developed using CoxBoost and plsRcox (CPM), and validated across multiple cohorts for its prognostic prediction capabilities, tumour microenvironment characterization, mutation landscape and immunotherapy response. We identified nine distinct tumour cell clusters, with Cluster 6 indicating an early developmental stage, high stemness and proliferative potential. The abundance of Clusters 0 and 6 increased from AAH to IAC, correlating with prognosis. The CPM model effectively distinguished prognosis in immunotherapy cohorts and predicted genomic alterations, chemotherapy drug sensitivity, and immunotherapy responsiveness. Key gene S100A16 in the CPM model was validated as an oncogene, enhancing LUAD cell proliferation, invasion and migration. The CPM model emerges as a novel biomarker for predicting prognosis and immunotherapy response in LUAD patients, with S100A16 identified as a potential therapeutic target.

Effects of Injectable Solutions on the Quality of Monocyte-Derived Dendritic Cells for Immunotherapy.

Therapeutic vaccines based on monocyte-derived dendritic cells have been shown to be promising strategies and may act as complementary treatments for viral infections, cancers, and, more recently, autoimmune diseases. Alpha-type-1-polarized dendritic cells (aDC1s) have been shown to induce type-1 immunity with a high capacity to produce interleukin-12p70 (IL-12p70). In the clinical use of cell-based therapeutics, injectable solutions can affect the morphology, immunophenotypic profile, and viability of cells before delivery and their survival after injection. In this sense, preparing a cell suspension that maintains the quality of aDC1s is essential to ensure effective immunotherapy. In the present study, monocytes were differentiated into aDC1s in the presence of IL-4 and GM-CSF. On day 5, the cells were matured by the addition of a cytokine cocktail consisting of IFN-α, IFN-γ, IL-1ß, TNF-α, and Poly I:C. After 48 hr, mature aDC1s were harvested and suspended in two different solutions: normal saline and Ringer's lactate. The maintenance of cells in suspension was evaluated after 4, 6, and 8 hr of storage. Cell viability, immunophenotyping, and apoptosis analyses were performed by flow cytometry. Cellular morphology was observed by electron microscopy, and the production of IL-12p70 by aDC1s was evaluated by ELISA. Compared with normal saline, Ringer's lactate solution was more effective at maintaining DC viability for up to 8 hr of incubation at 4 or 22°C.