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Many factors are associated with the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD); however, genetics and gut microbiota are representative factors. Recent studies have highlighted the link between host genes and the gut microbiota. Although there have been many studies on the separate effects of single nucleotide polymorphisms (SNPs) and gut bacteria on MASLD, few epidemiological studies have examined how SNPs and gut bacteria interact in the development and progression of MASLD. This study aimed to investigate the association between PNPLA3 rs738409, a representative MASLD-related SNP, and gut bacteria in MASLD using a cross-sectional study of the general population. The 526 participants (318 normal and 208 MASLD groups) were grouped into the PNPLA3 rs738409 SNP, CC, CG, and GG genotypes, and the differences in the gut microbiota were investigated in each group. The PNPLA3 rs738409 CC and CG genotypes were associated with decreased Blautia and Ruminococcaceae in the MASLD group. They were negatively correlated with controlled attenuation parameter levels, body mass index, serum blood glucose, and triglycerides. In contrast, there was no association between the normal and MASLD groups and the gut bacteria in the PNPLA3 rs738409, the GG genotype group. This finding implies that dietary interventions and probiotics may be more effective in preventing and treating MASLD in individuals with the PNPLA3 rs738409 CC and CG genotypes. In contrast, their efficacy may be limited in those with the GG genotype.

Background: Despite the favorable therapeutic efficacy observed with ICI monotherapy, the majority of non-small cell lung cancer (NSCLC) patients do not respond. Therefore, identifying patients who could optimally benefit from ICI treatment remains a challenge., Methods: Among 183 patients with advanced or recurrent NSCLC who received ICI monotherapy, we analyzed 110 patients whose pre- and post-treatment plasma samples were available. Seventy-three soluble immune mediators were measured at ICI initiation and 6 weeks later. To identify useful biomarkers, we analyzed the association of pre-treatment levels and on-treatment changes of soluble immune mediators with survival of patients. The associations of pre-treatment or on-treatment biomarkers with irAE development, PD-L1 expression, CD8+ TIL density, and neutrophil to lymphocyte ratio (NLR) were also analyzed., Results: Univariate analysis showed that pre-treatment biomarkers included 6 immune mediators, whereas on-treatment biomarkers included 8 immune mediators. Multivariate analysis showed that pre-treatment biomarkers included 4 immune mediators (CCL19, CCL21, CXCL5, CXCL10), whereas on-treatment biomarkers included 5 immune mediators (CCL7, CCL19, CCL23, CCL25, IL-32). IrAE development was associated with on-treatment change in CCL23. PD-L1 expression was associated with the pre-treatment levels of TNFSF13B and the on-treatment change in CCL25. CD8+ TIL density was associated with the pre-treatment CXCL10 level, whereas NLR was correlated with pre-treatment levels of CCL13 and CCL17., Conclusion: We identified several soluble immune mediators as pre-treatment and on-treatment biomarkers of survival in patients with NSCLC treated with ICI monotherapy. Some of these biomarkers were associated with other possible predictors, including irAE development, PD-L1 expression, CD8+ TIL density and NLR. Further large-scale studies are needed to establish biomarkers for patients with NSCLC who received ICI monotherapy., (© 2024. The Author(s).)

This study aimed to investigate the effect of Japanese dietary patterns on metabolic dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis. After excluding factors affecting the diagnosis of hepatic steatosis, 727 adults were analyzed as part of the Health Promotion Project. The dietary patterns of the participants were classified into rice, vegetable, seafood, and sweet based on their daily food intake. Liver stiffness measurements and controlled attenuation parameters were performed using FibroScan. Energy and nutrient intake were calculated using the Brief-type Self-administered Diet History Questionnaire. Univariate and multivariate analyses were used to identify the risk factors for liver fibrosis within the MASLD population. The vegetable group had significantly lower liver fibrosis indicators in the MASLD population than the rice group. The multivariate analysis identified a body mass index ≥ 25 kg/m 2 (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.01-1.83; p = 0.047) and HOMA-IR ≥ 1.6 (OR, 3.18; 95% CI, 1.74-5.78; p < 0.001) as risk factors for liver fibrosis, and vegetable group membership was a significant low-risk factor (OR, 0.38; 95% CI, 0.16-0.88; p = 0.023). The multivariate analysis of nutrients in low-risk foods revealed high intake of α-tocopherol (OR, 0.74; 95% CI, 0.56-0.99; p = 0.039) as a significant low-risk factor for liver fibrosis. This study suggests that a vegetable-based Japanese dietary pattern, through the antioxidant effects of α-tocopherol, may help prevent liver fibrosis in MASLD and the development of MASLD.

Neutrophil extracellular traps (NETs) released from neutrophils are related to cancer progression. However, the relationship between the therapeutic effects of immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-PD-L1 antibodies and plasma NET concentration in patients with non-small cell lung cancer (NSCLC) is poorly understood. In this study, concentrations of citrullinated histone H3 (CitH3), a surrogate marker of NETs, in plasma before/after treatment were examined in patients with advanced or recurrent NSCLC undergoing ICI treatment (n = 185). The clinical significances of NET levels before/after treatment and posttreatment changes were statistically evaluated. As a result, multivariate Cox analysis showed that high NET levels before treatment were statistically significant predictors of unfavorable overall survival (OS; p < 0.001, HR 1.702, 95% CI 1.356-2.137) and progression-free survival (PFS; p < 0.001, HR 1.566, 95% CI 1.323-1.855). The Kaplan-Meier curves showed significant separation between the high- and low-NET groups in OS ( p = 0.002) and PFS ( p < 0.001). Additionally, high NET levels after treatment were also significantly associated with worse OS ( p < 0.001) and PFS ( p < 0.001) by multivariate Cox analysis. Notably, the pretreatment NET levels were significantly correlated with the plasma levels of NET-related inflammatory cytokines, such as IL-6 and IL-8, and with NET-related gene expression and immune-suppressive profile in peripheral blood mononuclear cells. Our findings suggest that NETs released from activated neutrophils might reduce the clinical efficacy of ICIs in patients with NSCLC.

Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy characterized by advanced disease at diagnosis and a poor prognosis. Despite multimodal therapeutic approaches that include surgery, radiotherapy, and chemotherapy, an optimal treatment strategy remains elusive. Current developments in targeted therapies and immunotherapy offer promising avenues for improved outcomes, particularly for BRAF -mutant patients. However, challenges remain regarding overcoming drug resistance and developing effective treatments for BRAF -wild-type tumors. This comprehensive review examines the clinical and biological features of ATC, outlines the current standards of care, and discusses recent developments with a focus on the evolving role of radiotherapy. Moreover, it emphasizes the necessity of a multidisciplinary approach and highlights the urgent need for further research to better understand ATC pathogenesis and identify new therapeutic targets. Collaborative efforts, including large-scale clinical trials, are essential for translating these findings into improved patient outcomes.

Background: Few studies have reported reliable prognostic factors for immune checkpoint inhibitors (ICIs) in renal cell carcinoma (RCC). Therefore, we investigated prognostic factors in patients treated with ICIs for unresectable or metastatic RCC., Methods: We included 43 patients who received ICI treatment for RCC between January 2018 and October 2021. Blood samples were drawn before treatment, and 73 soluble factors in the plasma were analyzed using a bead-based multiplex assay. We examined factors associated with progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE) using the Chi-squared test, Kaplan-Meier method, and the COX proportional hazards model., Results: Patients exhibited a median PFS and OS of 212 and 783 days, respectively. Significant differences in both PFS and OS were observed for MMP1 (PFS, p < 0.001; OS, p = 0.003), IL-1β (PFS, p = 0.021; OS, p = 0.008), sTNFR-1 (PFS, p = 0.017; OS, p = 0.005), and IL-6 (PFS, p = 0.004; OS, p < 0.001). Multivariate analysis revealed significant differences in PFS for MMP1 (hazard ratio [HR] 5.305, 95% confidence interval [CI], 1.648-17.082; p = 0.005) and OS for IL-6 (HR 23.876, 95% CI, 3.426-166.386; p = 0.001). Moreover, 26 patients experienced irAE, leading to ICI discontinuation or withdrawal. MMP1 was significantly associated with irAE (p = 0.039)., Conclusion: MMP1 may be associated with severe irAE, and MMP1, IL-1β, sTNFR-1, and IL-6 could serve as prognostic factors in unresectable or metastatic RCC treated with ICIs. MMP1 and IL-6 were independent predictors of PFS and OS, respectively. Thus, inhibiting these soluble factors may be promising for enhancing antitumor responses in patients with RCC treated with ICIs., (© 2024. The Author(s).)

The selection of highly specific target antigens is critical for the development of clinically efficient and safe chimeric antigen receptors (CARs). In search of diagnostic marker for malignant mesothelioma (MM), we have established SKM9-2 monoclonal antibody (mAb) which recognizes a MM-specific molecule, sialylated Protein HEG homolog 1 (HEG1), with high specificity and sensitivity. In this study, to develop a novel therapeutic approach against MM, we generated SKM9-2 mAb-derived CARs that included the CD28 (SKM-28z) or 4-1BB (SKM-BBz) costimulatory domain. SKM-28z CAR-T cells showed continuous growth and enhanced Tim-3, LAG-3, and PD-1 expression in vitro, which might be induced by tonic signaling caused by self-activation; however, these phenotypes were not observed in SKM-BBz CAR-T cells. In addition, SKM-BBz CAR-T cells exhibited slightly stronger in vitro killing activity against MM cell lines than SKM-28z CAR-T cells. More importantly, only SKM-BBz CAR-T cells, but not SKM-28z CAR-T cells, significantly inhibited tumor growth in vivo in a MM cell line xenograft mouse model. Gene expression profiling and reporter assays revealed differential signaling pathway activation; in particular, SKM-BBz CAR-T cells exhibited enhanced NF-kB signaling and reduced NFAT activation. In addition, SKM-BBz CAR-T cells showed upregulation of early memory markers, such as TCF7 and CCR7, as well as downregulation of pro-apoptotic proteins, such as BAK1 and BID, which may be associated with phenotypical and functional differences between SKM-BBz and SKM-28z CAR-T cells. In conclusion, we developed novel SKM9-2-derived CAR-T cells with the 4-1BB costimulatory domain, which could provide a promising therapeutic approach against refractory MM., (© 2024 UICC.)

Accurately identifying neoantigens is crucial for developing effective cancer vaccines and improving tumor immunotherapy. Mass spectrometry-based immunopeptidomics has emerged as a promising approach to identifying human leukocyte antigen (HLA) peptides presented on the surface of cancer cells, but false-positive identifications remain a significant challenge. In this study, liquid chromatography-tandem mass spectrometry-based proteomics and next-generation sequencing were utilized to identify HLA-presenting neoantigenic peptides resulting from non-synonymous single nucleotide variations in tumor tissues from 18 patients with renal cell carcinoma or pancreatic cancer. Machine learning was utilized to evaluate Mascot identifications through the prediction of MS/MS spectral consistency, and four descriptors for each candidate sequence: the max Mascot ion score, predicted HLA binding affinity, aliphatic index and retention time deviation, were selected as important features in filtering out identifications with inadequate fragmentation consistency. This suggests that incorporating rescoring filters based on peptide physicochemical characteristics could enhance the identification rate of MS-based immunopeptidomics compared to the traditional Mascot approach predominantly used for proteomics, indicating the potential for optimizing neoantigen identification pipelines as well as clinical applications., Competing Interests: Tetsuro Sasada received honoraria from Chugai and Bristol Myers Squibb, and research funds from Taiho., (© 2024 The Authors.)

Introduction: Clinical roles of plasma IL-6 levels have been reported in patients with various cancers, including non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (ICIs). However, the roles of other IL-6 signaling components, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130), in the plasma have not been elucidated. Methods: Blood was collected from 106 patients with NSCLC before initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Plasma levels of IL-6, sIL-6R, sgp130, and their complexes were assessed by Cox regression hazard model to evaluate their clinical significance. The clinical role of IL-6 or IL-6R genetic polymorphisms was also analyzed. Results: Cox regression analysis showed that higher plasma IL-6 levels significantly predicted unfavorable overall survival (OS; hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.05-1.68, p = 0.012) in NSCLC patients treated with ICIs. However, plasma sIL-6R and sgp130 levels showed no prognostic significance ( p = 0.882 and p = 0.934, respectively). In addition, the estimated concentrations of binary IL-6:sIL-6R and ternary IL-6:sIL-6R:sgp130 complexes and their ratios (binary/ternary complex) were not significantly associated with OS ( p = 0.647, p = 0.727, and p = 0.273, respectively). Furthermore, the genetic polymorphisms of IL-6 (-634G>C) and IL-6R (48892A>C) showed no clinical role by Kaplan-Meier survival analysis ( p = 0.908 and p = 0.639, respectively). Discussion: These findings demonstrated the clinical significance of plasma levels of IL-6, but not of other IL-6 signaling components, sIL-6R and sgp130, suggesting that classical IL-6 signaling, but not trans-signaling, may be related to anti-tumor immune responses in cancer patients treated with ICIs., Competing Interests: YN has received honoraria from Ono, Takeda, Eli Lilly, Kyowa Kirin, Boehringer Ingelheim, AstraZeneca, and Bristol Myers Squibb, and research funding from Bristol Myers Squibb. SM has received honoraria from Ono. HS has received honoraria from Boehringer Ingelheim, Eli Lilly, Pfizer, AstraZeneca, Bristol Myers Squibb, Chugai, and Ono, and research funding from AstraZeneca, Bristol Myers Squibb, Chugai, and Ono. KA has received honoraria from AstraZeneca, MSD, Bristol Myers Squibb, Ono, and Chugai. TS has received honoraria from Chugai and Bristol Myers Squibb, and research funding from Taiho and BrightPath Biotherapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nakahara, Kouro, Motoyama, Miura, Fujita, Igarashi, Higashijima, Matsuo, Himuro, Wei, Horaguchi, Tsuji, Mano, Komahashi, Saito, Azuma and Sasada.)