Clinical and Experimental Medicine最新文献

Anti-tumor immunotherapy was rediscovered and rejuvenated in the last two decades with the discovery of CTLA-4, PD-1 and PD-L1 and the roles in inhibiting immune function and tumor evasion of anti-tumor immune response. Following the approval of the first checkpoint inhibitor ipilimumab against CTLA-4 in melanoma in 2011, there has been a rapid development of tumor immunotherapy. Furthermore, additional positive and negative molecules among the T-cell regulatory systems have been identified that that function to fine tune the stimulatory or inhibitory immune cells and modulate their functions (checkpoint modulators). Many strategies are being explored to target macrophages, NK-cells, cytotoxic T-cells, fibroblasts, endothelial cells, cytokines and molecules involved in tumor tolerance and microbiome. Similar to agents that target checkpoint modulators, these newer targets have the potential to synergize with other classes of immunotherapeutic agents and importantly may overcome the resistance to other immunotherapies. In order to better understand the mechanism of action of all major classes of immunotherapy, design clinical trials taking advantage of different types of immunotherapeutic agents and use them rationally in clinical practice either in combination or in sequence, we propose the group all immunotherapies into three generations: with CTLA-4, PD-1 and PD-L1 inhibitors as the first generation, agents that target the checkpoint modulators as the second generation, while those that target TME as the third generation. This review discusses all three generations of immunotherapy in oncology, their mechanism of actions, major clinical trial results and indication, strategies for future clinical trial designs and rational clinical applications.

Introduction Recently, immune cells within the tumor microenvironment (TME) have become crucial in regulating cancer progression and treatment responses. The dynamic interactions between tumors and immune cells are emerging as a promising strategy to activate the host's immune system against various cancers. The development and progression of hepatocellular carcinoma (HCC) involve complex biological processes, with the role of the TME and tumor phenotypes still not fully understood. Therefore, it is essential to investigate the importance of immune cell homeostasis in HCC. Additionally, understanding the molecular mechanisms and biological functions underlying tumor-immune cell interactions is increasingly recognized as vital for improving therapeutic outcomes in clinical settings. Methods A total of 790 HCC samples were selected from public databases and real-world independent clinical cohorts. Machine learning methods, focusing on immune-related indicators, were applied to these samples. The Boruta algorithm was employed to develop an ICI score, which was used to assess patient prognosis and predict responses to immunotherapy. Additionally, a new immune subtype analysis of HCC was performed. Cellular-level experiments confirmed the interaction between TME-related factors and the tumor microenvironment in HCC. To further validate the predictive power of the ICI score, a clinical cohort study was conducted at an independent clinical center. Results By evaluating immune gene expression levels, immune cell abundance, Immunescore, and Stromalscore, we initially identified three distinct immune subtypes of HCC, each showing significant differences in survival rates and heterogeneity. Subsequently, DEGs from 1022 immune subtypes were used to classify HCC samples into three immune genotypes, each characterized by distinct prognosis and tumor immune microenvironment (TIME) profiles. Furthermore, we developed the ICI score, a novel immunophenotyping method for HCC, which revealed significant variations based on gender, stage, progression, and DNA mutation profiles (p < 0.05). The ICI score also effectively predicted responses to immunotherapies, particularly through the chemokine signaling, focal adhesion, and JAK/STAT signaling pathways. Conclusion This research demonstrated that TME and immunophenotyping clusters can enhance prognostic accuracy for HCC patients. The independent prognostic indicators identified underscore the connection between tumor phenotype and the immune environment in HCC.

Adoptive cell therapy (ACT) using natural killer (NK) cells has emerged as a promising therapeutic strategy for acute myeloid leukemia (AML), addressing challenges such as chemotherapy resistance and high relapse rates. Over the years, clinical trials and studies have explored various sources of NK cells, including ex vivo expanded NK cell lines, CAR-NK cells, peripheral blood-derived NK cells, and umbilical cord blood-derived NK cells. These therapies have demonstrated varying degrees of therapeutic efficacy, ranging from transient anti-leukemia activity to sustained remission in select patient groups. Toxicity profiles have generally shown favorable safety outcomes, with minimal incidence of severe adverse effects such as cytokine release syndrome (CRS) or graft-versus-host disease (GVHD). However, persistent challenges remain, including limited NK cell persistence, relapse, and heterogeneity in patient responses. This review provides a comprehensive analysis of clinical outcomes and toxicity profiles provided from clinical trials, clinical studies and case reports conducted in the last 15 years to judge on the efficacy, safety and applicability of using NK cells for ACT of AML. Our review highlights the significant potential of NK cell-based therapies for AML, while addressing the technical and biological challenges that must be overcome to enhance their efficacy and safety.

Multiple myeloma (MM) is characterized by clonal plasma cell proliferation in the bone marrow, challenging prognosis prediction. We developed a gene-pairing prognostic risk model using m6A regulatory genes and a nested LASSO method. A cutoff of - 0.133 categorized MM samples into high-risk and low-risk groups. The model showed strong prognostic performance in 2088 newly diagnosed MM samples and predicted response to combination therapy (daratumumab, carfilzomib, lenalidomide, and dexamethasone) in patients who failed or relapsed from bortezomib-containing regimens, with an AUC of 0.9. It distinguished between smoldering MM and MM (cutoff: - 0.45) and between MM and plasma cell leukemia (cutoff: 0.0857). Single-cell analysis revealed higher risk scores at relapse. Combining MM cell lines and sample data, we identified potential drugs and targets (ADAT2 and NUP153) effective against high-risk MM. Integrating the m6A risk model with the International Staging System (ISS) enhanced stratification accuracy. These insights support precision treatment of MM.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disorder closely linked to metabolic syndrome. Identifying novel, easily measurable biomarkers could significantly enhance the diagnosis and management of NAFLD in clinical settings. Recent studies suggest that immunoinflammatory biomarkers-specifically, the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR)-may offer diagnostic value for NAFLD. However, the effectiveness of these biomarkers has not been comprehensively assessed in this patient population. This systematic review and meta-analysis aimed to evaluate the association between these immunoinflammatory biomarkers and NAFLD. As of August 8, 2024, databases including PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus were systematically searched to compare NLR, PLR, and LMR levels in NAFLD patients and healthy controls. Study quality was assessed using the Newcastle-Ottawa Scale, and standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated (PROSPERO registry number: CRD42024580812). A total of 20 studies were included in the meta-analysis. Results indicated that NAFLD patients had significantly higher NLR levels (SMD = 0.43; 95% CI 0.28-0.58; p < 0.001) and lower PLR levels (SMD = - 0.29; 95% CI - 0.41 to - 0.17; p < 0.001) compared to controls. However, no significant difference in LMR was observed between NAFLD patients and controls(SMD = 0.08; 95% CI - 0.00 to 0.17; p = 0.051). These findings suggest that NLR and PLR may hold promise as diagnostic markers for NAFLD, while LMR appears to have limited diagnostic utility. Further research is warranted to explore the potential role of these biomarkers in tracking disease progression.

Upon stimulation and activation, mast cells (MCs) release soluble mediators, including histamine, proteases, and cytokines. These mediators are often stored within cytoplasmic granules in MCs and may be released in a granulated form. The secretion of cytokines and chemokines occurs within hours following activation, with the potential to result in chronic inflammation. In addition to their role in allergic inflammation, MCs are components of the tumor microenvironment (TME). MicroRNAs (miRNAs) are small RNA molecules that do not encode proteins, but regulate post-transcriptional gene expression by binding to the 3' non-coding regions of mRNAs. This plays a crucial role in the function of MC, including the key processes of MC proliferation, maturation, apoptosis, and activation. It has been demonstrated that miRNAs are also present in extracellular vesicles (EVs) secreted by MCs. EVs derived from MCs mediate intercellular communication by carrying miRNAs, affecting various diseases including allergic diseases, intestinal disorders, neuroinflammation, and tumors. These findings provide important insights into the therapeutic mechanisms and targets of miRNAs in MCs that affect diseases. This review discusses the relevance of miRNA production by MCs in regulating their own activity and the effect of miRNAs putatively produced by other cells in the control of MC activity and their participation in selected pathologies.

The diagnostic criteria for Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) and Metabolic Associated Steatotic Liver Disease (MASLD) aim to refine the classification of fatty liver diseases previously grouped under Non-Alcoholic Fatty Liver Disease (NAFLD). This study evaluates the applicability of the MAFLD and MASLD frameworks in NAFLD patients, exploring their clinical utility in identifying high-risk patients. A total of 369 NAFLD patients were assessed using MAFLD and MASLD diagnostic criteria. Baseline characteristics, metabolic profiles, hepatic fibrosis, and cardiovascular risks were compared across the groups. Among NAFLD patients, 97.55% (n = 359) met MASLD criteria, and 97.01% (n = 357) fulfilled MAFLD criteria. Both frameworks MAFLD and MASLD captured overlapping populations, with MASLD encompassing slightly more cases. No significant differences were observed in metabolic risk factors, fibrosis indices (APRI, FIB-4, NAFLD fibrosis score), or cardiovascular risk (10-year ASCVD score). A small subset of lean NAFLD patients (10 cases) with distinct profiles remained uncategorized by either framework. Pure NAFLD cases (n = 10) were with mild insulin resistance (HOMA-IR: 3.07 ± 0.33) and slightly elevated LDL (102.5 ± 42.87 mg/dL), while fibrosis indices indicated low fibrosis risk. Steatosis indices supported the diagnosis of early-stage NAFLD with preserved liver function. These patients do not meet the criteria for inclusion in the MAFLD or MASLD frameworks, highlighting a gap in the current diagnostic systems. MAFLD and MASLD criteria align closely with NAFLD in capturing patients with metabolic risk with MASLD-enhanced inclusivity. Further refinement is required to address heterogeneity, particularly in lean NAFLD patients. Hypertension prevalence was comparable (17.4% in NAFLD, 18.2% in MAFLD, 17.8% in MASLD; p = 0.960), as was diabetes mellitus (36.7%, 37.8%, and 37.6%, respectively; p = 0.945). Body mass index was also similar across groups, with medians of 33.25, 33.6, and 33.4 kg/m² (p = 0.731). Non-invasive markers of hepatic fibrosis, including APRI, FIB-4, and NAFLD fibrosis scores, did not differ significantly, with median FIB-4 scores around 1.05 (p = 0.953). Similarly, were the results of hepatic steatosis index and ASCVD score.

Purpose: STING (stimulator of interferon genes) is involved in viral and bacterial defense through interferon pathway and innate immunity. Increased susceptibility to infection is a common manifestation of multiple myeloma (MM). Thus, we aimed to explore the clinical significance and possible mechanism of STING in MM.

Materials and methods: Immunohistochemistry and qPCR were used to detect STING expression in the bone marrow of MM patients, and flow cytometry was used to detect the amount of intracellular STING. All data were analyzed with clinical characteristics.

Results: STING expression was remarkably reduced in MM tissues compared to normal tissues and was not associated with stage. Multivariate analysis identified STING as an independent prognostic factor in MM patients (P = 0.001). In the bortezomib-containing regimens, patients with low STING expression were more difficult to achieve remission. A model incorporating STING and m-SMART significantly improved the predictive accuracy of overall survival in bortezomib regimens (AUC, 0.511 to 0.630, P = 0.044). Bortezomib efficacy has been reported to correlate with activated immunity, but the low expression group manifested as immune apathy. Although baseline characteristics showed intergroup differences in infection, the low expression group had an increased proportion of bacterial infections (1.7-fold) and a prolonged duration of antibiotic/antifungal medication (3.55 additional days); these patients were accompanied by a decreased neutrophil-to-lymphocyte ratio (NLR) and rarely activated neutrophils and leukocytes. The intracellular STING ratio was also defective in neutrophil-dominated leukocytes.

Conclusion: Our study revealed that STING had a strong association with bortezomib and could serve as a potential target for immunotherapy in multiple myeloma.

Lung cancer is one of the major causes of cancer morbidity and mortality. Subtyping of non-small cell lung cancer is necessary owing to different treatment options. This study is to evaluate the value of immunohistochemical expression of glypican-1 in the diagnosis of lung squamous cell carcinoma (SCC). This retrospective study included a total of 68 cases, of which 36 were diagnosed as SCC and 32 as adenocarcinoma (ADC). Furthermore, glypican-1 expression was compared with the expressions of p63, thyroid transcription factor-1 (TTF-1), and napsin A. All cases of SCC except one showed positive immunostaining to glypican-1; 35/36 (97.2%) cases, and predominantly scored 3 + . While only 5 cases of ADC showed positive immunostaining to glypican-1, having a score of 1 + or 2 + . The difference between glypican-1 expression of the two tumor types was highly significant (p value < 0.001). The sensitivity, specificity, and overall accuracy of glypican-1 expression for differentiating lung SCC from ADC were 97.2%, 84.4%, and 91.2%, respectively. The sensitivity of glypican-1 is more than p63 in the diagnosis of lung SCC. Glypican-1 can be added as a new diagnostic marker to help in the accurate discrimination between poorly differentiated lung SCC and solid predominant adenocarcinoma cases.

IL-27 is structurally an immune-enhancing and pleiotropic two-chain cytokine associated with IL-12 and IL-6 families. IL-27 contains two subunits, namely IL-27p28 and EBI3. A heterodimer receptor of IL-27, composed of IL27Rα (WSX1) and IL6ST (gp130) chains, mediates the IL-27 function following the activation of STAT1 and STAT3 signaling pathways. Specifically, IL-27 is identified as augmenting cytokine of immune responses, including Th1 cell differentiation, TCd4 + cell proliferation, and IFN-γ production with the help of IL-12. According to several published studies, due to the pro-inflammatory or anti-inflammatory functions of cytokine related to the biological context in various disorders and diseases, IL-27 has been considered a complex regulator of the immune system. Surprisingly, the dual role of IL-27, the same as the double-edged sword, has also been evidenced in clinical models of various hematological or solid tumors. Predominantly, Il-27 applies anti-tumor functions by inducing the responses of a cytotoxic T lymphocyte (CTL) and Th1 and suppressing the growth, proliferation, angiogenesis, invasiveness, metastasis, and survival of tumor cells. On the other hand, IL-27 may also play a protumor role in cancers and induce tumor progression. The current update study aimed to summarize the protumor anti-tumor and biological functions of IL-27 in different hematological malignancies and solid tumors.