Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study. METHODS: This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every three weeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1. RESULTS: Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 28 (46.7%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors. CLINICALTRIALS: gov NCT04169672.

Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis.

BACKGROUND: Macrophages play a crucial role in atherosclerotic plaque formation, and the death of macrophages is a vital factor in determining the fate of atherosclerosis. GSDMD (gasdermin D)-mediated pyroptosis is a programmed cell death, characterized by membrane pore formation and inflammatory factor release. METHODS: ApoE-/- and Gsdmd-/- ApoE-/- mice, bone marrow transplantation, and AAV-F4/80-shGSDMD were used to examine the effect of macrophage-derived GSDMD on atherosclerosis. Single-cell RNA sequencing was used to investigate the changing profile of different cellular components and the cellular localization of GSDMD during atherosclerosis. RESULTS: First, we found that GSDMD is activated in human and mouse atherosclerotic plaques and Gsdmd-/- attenuates the atherosclerotic lesion area in high-fat diet-fed ApoE-/- mice. We performed single-cell RNA sequencing of ApoE-/- and Gsdmd-/- ApoE-/- mouse aortas and showed that GSDMD is principally expressed in atherosclerotic macrophages. Using bone marrow transplantation and AAV-F4/80-shGSDMD, we identified the potential role of macrophage-derived GSDMD in aortic pyroptosis and atherosclerotic injuries in vivo. Mechanistically, GSDMD contributes to mitochondrial perforation and mitochondrial DNA leakage and subsequently activates the STING (stimulator of interferon gene)-IRF3 (interferon regulatory factor 3)/NF-κB (nuclear factor kappa B) axis. Meanwhile, GSDMD regulates the STING pathway activation and macrophage migration via cytokine secretion. Inhibition of GSDMD with GSDMD-specific inhibitor GI-Y1 can effectively alleviate the progression of atherosclerosis. CONCLUSIONS: Our study has provided a novel macrophage-derived GSDMD mechanism in the promotion of atherosclerosis and demonstrated that GSDMD can be a potential therapeutic target for atherosclerosis.

A blueprint for tumor-infiltrating B cells across human cancers.

B lymphocytes are essential mediators of humoral immunity and play multiple roles in human cancer. To decode the functions of tumor-infiltrating B cells, we generated a B cell blueprint encompassing single-cell transcriptome, B cell-receptor repertoire, and chromatin accessibility data across 20 different cancer types (477 samples, 269 patients). B cells harbored extraordinary heterogeneity and comprised 15 subsets, which could be grouped into two independent developmental paths (extrafollicular versus germinal center). Tumor types grouped into the extrafollicular pathway were linked with worse clinical outcomes and resistance to immunotherapy. The dysfunctional extrafollicular program was associated with glutamine-derived metabolites through epigenetic-metabolic cross-talk, which promoted a T cell-driven immunosuppressive program. These data suggest an intratumor B cell balance between extrafollicular and germinal-center responses and suggest that humoral immunity could possibly be harnessed for B cell-targeting immunotherapy.

Integration of single-nucleus and exosome RNA sequencing dissected inter-cellular communication and biomarkers in pancreatic ductal adenocarcinoma.

Background: Mounting evidence underscores the importance of cell communication within the tumor microenvironment, which is pivotal in tumor proliferation, invasion, and metastasis. Exosomes play a crucial role in cell-to-cell communication. Although single-cell RNA sequencing (scRNA-seq) provides insights into individual cell transcriptional characteristics, it falls short of comprehensively capturing exosome-mediated intercellular communication. Method: We analyzed Pancreatic Ductal Adenocarcinoma (PDAC) tissues, separating supernatant and precipitate for exosome purification and single-cell nucleus suspension. We then constructed Single-nucleus RNA sequencing (snRNA-seq) and small RNA-seq libraries from these components. Our bioinformatic analysis integrated these sequences with ligand-receptor analysis and public miRNA data to map the cell communication network. Results: We established intercellular communication networks using bioinformatic analysis to track exosome miRNA effects and ligand-receptor pairs. Significantly, hsa-miR-1293 emerged as a prognostic biomarker for pancreatic cancer, linked to immune evasion, increased myeloid-derived suppressor cells, and poorer prognosis. Targeting this miRNA may enhance anti-tumor immunity and improve outcomes. Conclusion: Our study offers a novel approach to constructing intercellular communication networks using snRNA-seq and exosome-small RNA sequencing. By integrating miRNA tracing with ligand-receptor analysis, we illuminate the complex interactions in the pancreatic cancer microenvironment, highlighting the pivotal role of miRNAs and identifying potential biomarkers and therapeutic targets.

Preliminary Mechanism of Glial Maturation Factor ß on Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.

Recent evidence suggests that glia maturation factor ß (GMFß) is important in the pathogenesis of pulmonary arterial hpertension (PAH), but the underlying mechanism is unknown. To clarify whether GMFß can be involved in pulmonary vascular remodeling and to explore the role of the IL-6-STAT3 pathway in this process, the expression of GMFß in PAH rats is examined and the expression of downstream molecules including periostin (POSTN) and interleukin-6 (IL-6) is measured using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The location and expression of POSTN is also tested in PAH rats using immunofluorescence. It is proved that GMFß is upregulated in the lungs of PAH rats. Knockout GMFß alleviated the MCT-PAH by reducing right ventricular systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), and pulmonary vascular remodeling. Moreover, the inflammation of the pulmonary vasculature is ameliorated in PAH rats with GMFß absent. In addition, the IL-6-STAT3 signaling pathway is activated in PAH; knockout GMFß reduced POSTN and IL-6 production by inhibiting the IL-6-STAT3 signaling pathway. Taken together, these findings suggest that knockout GMFß ameliorates PAH in rats by inhibiting the IL-6-STAT3 signaling pathway.

Intratumoral CD38+CD19+B cells associate with poor clinical outcomes and immunosuppression in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The widespread involvement of tumor-infiltrating B cells highlights their potential role in tumor behavior. However, B cell heterogeneity in PDAC remains unexplored. Studying TIL-Bs in PDAC aims to identify new treatment strategies. METHODS: We performed single-cell RNA sequencing to study the heterogeneity of B cells in PDAC. The prognostic and immunologic value of the identified CD38+ B cells was explored in FUSCC (n = 147) and TCGA (n = 176) cohorts. Flow cytometry was conducted to characterize the relationship between CD38+ B cells and other immune cells, as well as their phenotypic features. In vitro and in vivo experiments were performed to assess the putative effect of CD38+ B cells on antitumor immunity. FINDINGS: The presence of CD38+ B cells in PDAC was associated with unfavorable clinicopathological features and poorer overall survival (p < 0.001). Increased infiltration of CD38+ B cells was accompanied by reduced natural killer (NK) cells (p = 0.021) and increased regulatory T cells (p = 0.016). Molecular profiling revealed high expression of IL-10, IL-35, TGF-ß, GZMB, TIM-1, CD5 and CD21, confirming their putative regulatory B cell-like features. Co-culture experiments demonstrated suppression of NK cell cytotoxicity by CD38+ B cell-derived IL-10 (p < 0.001). Finally, in vivo experiments suggested adoptive transfer of CD38+ B cells reduced antitumor immunity and administration of a CD38 inhibitor hampered tumor growth (p < 0.001). INTERPRETATION: We discovered regulatory B cell-like CD38+ B cell infiltration as an independent prognostic factor in PDAC. The use of CD38 inhibitor may provide new possibilities for PDAC immunotherapy. FUNDING: This study was supported by the National Natural Science Foundation of China (U21A20374), Shanghai Municipal Science and Technology Major Project (21JC1401500), Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057), Special Project for Clinical Research in the Health Industry of the Shanghai Health Commission (No. 20204Y0265) and Natural Science Foundation of Shanghai (23ZR1479300).

Histone lactylation: from tumor lactate metabolism to epigenetic regulation.

The Warburg Effect is one of the most well-known cancer hallmarks. This metabolic pattern centered on lactate has extremely complex effects on various aspects of tumor microenvironment, including metabolic remodeling, immune suppression, cancer cell migration, and drug resistance development. Based on accumulating evidence, metabolites are likely to participate in the regulation of biological processes in the microenvironment and to form a feedback loop. Therefore, further revealing the key mechanism of lactate-mediated oncological effects is a reasonable scientific idea. The discovery and refinement of histone lactylation in recent years has laid a firm foundation for the above idea. Histone lactylation is a post-translational modification that occurs at lysine sites on histones. Specific enzymes, known as "writers" and "erasers", catalyze the addition or removal, respectively, of lactacyl group at target lysine sites. An increasing number of investigations have reported this modification as key to multiple cellular procedures. In this review, we discuss the close connection between histone lactylation and a series of biological processes in the tumor microenvironment, including tumorigenesis, immune infiltration, and energy metabolism. Finally, this review provides insightful perspectives, identifying promising avenues for further exploration and potential clinical application in this field of research.

Pirfenidone alleviates fibrosis by acting on tumour-stroma interplay in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a 5-year survival rate of 12%. The abundant mesenchyme is partly responsible for the malignancy. The antifibrotic therapies have gained attention in recent research. However, the role of pirfenidone, an FDA-approved drug for idiopathic pulmonary fibrosis, remains unclear in PDAC. METHODS: Data from RNA-seq of patient-derived xenograft (PDX) models treated with pirfenidone were integrated using bioinformatics tools to identify the target of cell types and genes. Using confocal microscopy, qRT-PCR and western blotting, we validated the signalling pathway in tumour cells to regulate the cytokine secretion. Further cocultured system demonstrated the interplay to regulate stroma fibrosis. Finally, mouse models demonstrated the potential of pirfenidone in PDAC. RESULTS: Pirfenidone can remodulate multiple biological pathways, and exerts an antifibrotic effect through inhibiting the secretion of PDGF-bb from tumour cells by downregulating the TGM2/NF-kB/PDGFB pathway. Thus, leading to a subsequent reduction in collagen X and fibronectin secreted by CAFs. Moreover, the mice orthotopic pancreatic tumour models demonstrated the antifibrotic effect and potential to sensitise gemcitabine. CONCLUSIONS: Pirfenidone may alter the pancreatic milieu and alleviate fibrosis through the regulation of tumour-stroma interactions via the TGM2/NF-kB/PDGFB signalling pathway, suggesting potential therapeutic benefits in PDAC management.

CPT1B maintains redox homeostasis and inhibits ferroptosis to induce gemcitabine resistance via the KEAP1/NRF2 axis in pancreatic cancer.

BACKGROUND: Although we have made progress in treatment and have increased the 5-year survival by ≤30% in pancreatic cancer, chemotherapy resistance remains a major obstacle. However, whether reprogrammed lipid metabolism contributes to chemoresistance still needs to be further studied. METHODS: Gene expression was determined using Western blotting and quantitative reverse transcription polymerase chain reaction. Cell cloning formation assay, Cell Counting Kit-8, EdU assay, wound healing assay, transwell assay, and flow cytometry were used to detect apoptosis, cell proliferation capacity, migration capacity, and cytotoxicity of gemcitabine. Confocal fluorescence microscopy, transmission electron microscopy, etc., were used to detect the changes in intracellular reactive oxygen species, glutathione, lipid peroxidation level, and cell morphology. An animal study was performed to evaluate the effect of CPT1B knockdown on tumor growth and gemcitabine efficacy. RESULTS: In our study, we observed that the CPT1B expression level was higher in pancreatic ductal adenocarcinoma tissues than in normal tissues and correlated with a low rate of survival. Moreover, silencing of CPT1B significantly suppressed the proliferative ability and metastasis of pancreatic cancer cells. Furthermore, we discovered that CPT1B interacts with Kelch-like ECH-associated protein 1, and CPT1B knockdown led to decreased NRF2 expression and ferroptosis induction. In addition, CPT1B expression increased after gemcitabine treatment, and it was highly expressed in gemcitabine-resistant pancreatic ductal adenocarcinoma cells. Finally, we discovered that ferroptosis induced by CPT1B knockdown enhanced the gemcitabine toxicity in pancreatic ductal adenocarcinoma. CONCLUSION: CPT1B may act as a promising target in treating patients with gemcitabine-resistant pancreatic ductal adenocarcinoma .

Prospective observational study on biomarkers of response in pancreatic ductal adenocarcinoma.

Adjuvant chemotherapy benefits patients with resected pancreatic ductal adenocarcinoma (PDAC), but the compromised physical state of post-operative patients can hinder compliance. Biomarkers that identify candidates for prompt adjuvant therapy are needed. In this prospective observational study, 1,171 patients with PDAC who underwent pancreatectomy were enrolled and extensively followed-up. Proteomic profiling of 191 patient samples unveiled clinically relevant functional protein modules. A proteomics-level prognostic risk model was established for PDAC, with its utility further validated using a publicly available external cohort. More importantly, through an interaction effect regression analysis leveraging both clinical and proteomic datasets, we discovered two biomarkers (NDUFB8 and CEMIP2), indicative of the overall sensitivity of patients with PDAC to adjuvant chemotherapy. The biomarkers were validated through immunohistochemistry on an internal cohort of 386 patients. Rigorous validation extended to two external multicentic cohorts-a French multicentric cohort (230 patients) and a cohort from two grade-A tertiary hospitals in China (466 patients)-enhancing the robustness and generalizability of our findings. Moreover, experimental validation through functional assays was conducted on PDAC cell lines and patient-derived organoids. In summary, our cohort-scale integration of clinical and proteomic data demonstrates the potential of proteomics-guided prognosis and biomarker-aided adjuvant chemotherapy for PDAC.

Surufatinib plus toripalimab in patients with advanced neuroendocrine tumours and neuroendocrine carcinomas: An open-label, single-arm, multi-cohort phase II trial.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib revealed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumours in a phase I study. PATIENTS AND METHODS: This was an open-label, single-arm, multi-cohort phase II study in China. Patients with advanced neuroendocrine tumours (NETs) or neuroendocrine carcinomas (NECs) or mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) who had failed or were intolerable of standard treatment were given surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every 3 weeks). Primary end-point was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end-points included duration of response (DoR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled into two cohorts by tumour types (NET, n = 19; NEC-MiNEN, n = 21). ORRs (95% CIs) were 21.1% (6.1-45.6) and 23.8% (8.2-47.2) in the NET and NEC-MiNEN cohorts, respectively. Median DoR was 7.1 months (6.9-not evaluable [NE]) and 4.1 months (3.0-NE), respectively. Median PFS was 9.6 months (4.1-NE) and 4.1 months (1.5-5.5); median OS was 27.3 (15.3-NE) and 10.9 months (9.1-14.6), respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 18 (45.0%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed antitumour activity and a tolerable safety profile in patients with previously treated NETs/NECs/MiNENs. Further study of this combination regimen is ongoing for advanced NECs, for which current therapeutic options remain limited. CLINICALTRIALS: gov: NCT04169672.

PP2A complex disruptor SET prompts widespread hypertranscription of growth-essential genes in the pancreatic cancer cells.

Hyperactivation of the oncogenic transcription reflects the epigenetic plasticity of the cancer cells. Su(var)3-9, enhancer of zeste, Trithorax (SET) was described as a nuclear factor that stimulated transcription from the chromatin template. However, the mechanisms of SET-dependent transcription are unknown. Here, we found that overexpression of SET and CDK9 induced very similar transcriptome signatures in multiple cancer cell lines. SET localized in the transcription start site (TSS)-proximal regions and supported the RNA transcription. SET specifically bound the PP2A-C subunit and induced PP2A-A subunit repulsion from the C subunit, which indicated the role of SET as a PP2A-A/C complex disruptor in the TSS-proximal regions. Through blocking PP2A activity, SET assisted CDK9 to maintain Pol II CTD phosphorylation and activated mRNA transcription. Our findings position SET as a key factor that modulates chromatin PP2A activity, promoting the oncogenic transcription in the pancreatic cancer.

NUSAP1 promotes pancreatic ductal adenocarcinoma progression by drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and its molecular mechanisms are unclear. Nucleolar and spindle-associated protein 1 (NUSAP1), an indispensable mitotic regulator, has been reported to be involved in the development of several types of tumors. The biological function and molecular mechanism of NUSAP1 in PDAC remain controversial. This study explored the effects and mechanism of NUSAP1 in PDAC. METHODS: Differentially expressed genes (DEGs) were screened. A protein‒protein interaction (PPI) network was constructed to identify hub genes. Experimental studies and tissue microarray (TMA) analysis were performed to investigate the effects of NUSAP1 in PDAC and explore its mechanism. RESULTS: Network analysis revealed that NUSAP1 is an essential hub gene in the PDAC transcriptome. Genome heterogeneity analysis revealed that NUSAP1 is related to tumor mutation burden (TMB), loss of heterozygosity (LOH) and homologous recombination deficiency (HRD) in PDAC. NUSAP1 is correlated with the levels of infiltrating immune cells, such as B cells and CD8 T cells. High NUSAP1 expression was found in PDAC tissues and was associated with a poor patient prognosis. NUSAP1 promoted cancer cell proliferation, migration and invasion, drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation. CONCLUSIONS: NUSAP1 is an essential hub gene that promotes PDAC progression and leads to a dismal prognosis by drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation.

FGF19 promotes nasopharyngeal carcinoma progression by inducing angiogenesis via inhibiting TRIM21-mediated ANXA2 ubiquitination.

PURPOSE: Nasopharyngeal carcinoma (NPC) has characteristics of high invasion and early metastasis. Most NPC patients present with locoregionally advanced illness when first diagnosed. Therefore, it is urgent to discover NPC biomarkers. Fibroblast growth Factor 19 (FGF19) plays a role in various physiological or pathological processes, including cancer. In this research, we discovered the importance of FGF19 in NPC, and clarified its role in tumour angiogenesis. METHODS: Western blotting, immunohistochemistry and ELISA were used to investigate FGF19 expression in NPC. Then we took CCK8, colony formation, Transwell and wound healing assays to identify the influence of FGF19 on NPC malignant behaviours. The proliferative and metastatic capacity of FGF19 were evaluated in nude mice and zebrafish. The role of FGF19 in angiogenesis was investigated by tube formation and Matrigel plug angiogenesis assays. We then evaluated the variation in Annexin A2(ANXA2) levels with the treatment of FGF19. Lastly, co-immunoprecipitation and ubiquitination assays were performed to identify the mechanisms involved. RESULTS: FGF19 levels were elevated in tissues and serum of NPC patients and were associated with poor clinical stages. High expression of FGF19 promoted NPC malignant behaviours. In particular, FGF19 expression was correlated with microvessel density in tissues and NPC-derived FGF19 could accelerate angiogenesis in vitro and in vivo. Mechanistically, FGF19 influenced ANXA2 expression to promote angiogenesis. Moreover, tripartite motif-containing 21(TRIM21) interacted with ANXA2 and was responsible for ANXA2 ubiquitination. CONCLUSION: FGF19 promoted NPC angiogenesis by inhibiting TRIM21-mediated ANXA2 ubiquitination. It may serve as a noninvasive biomarker for NPC and provides new insights for therapy.

GMFB/AKT/TGF-ß3 in Müller cells mediated early retinal degeneration in a streptozotocin-induced rat diabetes model.

Retinal degeneration, characterized by Müller cell gliosis and photoreceptor apoptosis, is considered an early event in diabetic retinopathy (DR). Our previous study proposed that GMFB may mediate diabetic retinal degeneration. This study identified GMFB as a sensitive and functional gliosis marker for DR. Compared to the wild type (WT) group, Gmfb knockout (KO) significantly improved visual function, attenuated gliosis, reduced the apoptosis of neurons, and decreased the mRNA levels of tumor necrosis factor α (Tnf-α) and interleukin-1ß (Il-1ß) in diabetic retinas. Tgf-ß3 was enriched by hub genes using RNA sequencing in primary WT and KO Müller cells. Gmfb KO significantly upregulated the transforming growth factor (TGF)-ß3 protein level via the AKT pathway. The protective effect of TGF-ß3 in the vitreous resulted in significantly improved visual function and decreased the number of apoptotic cells in the diabetic retina. The protection of Gmfb KO in primary Müller cells against high glucose (HG)-induced photoreceptor apoptosis was partially counteracted by TGF-ß3 antibody and administration of TGFBR1/2 inhibitors. Nuclear receptor subfamily 3 group C member 1 (NR3C1) binds to the promoter region of Gmfb and regulates Gmfb mRNA at the transcriptional level. NR3C1 was increased in the retinas of early diabetic rats but decreased in the retinas of late diabetic rats. N'-[(1E)-(3-Methoxyphenyl)Methylene]-3-Methyl-1H-Pyrazole-5-Carbohydrazide (DS-5) was identified as an inhibitor of GMFB, having a protective role in DR. We demonstrated that GMFB/AKT/TGF-ß3 mediated early diabetic retinal degeneration in diabetic rats. This study provides a novel therapeutic strategy for treating retinal degeneration in patients with DR.

Novel research and future prospects of artificial intelligence in cancer diagnosis and treatment.

Research into the potential benefits of artificial intelligence for comprehending the intricate biology of cancer has grown as a result of the widespread use of deep learning and machine learning in the healthcare sector and the availability of highly specialized cancer datasets. Here, we review new artificial intelligence approaches and how they are being used in oncology. We describe how artificial intelligence might be used in the detection, prognosis, and administration of cancer treatments and introduce the use of the latest large language models such as ChatGPT in oncology clinics. We highlight artificial intelligence applications for omics data types, and we offer perspectives on how the various data types might be combined to create decision-support tools. We also evaluate the present constraints and challenges to applying artificial intelligence in precision oncology. Finally, we discuss how current challenges may be surmounted to make artificial intelligence useful in clinical settings in the future.

Targeting neoadjuvant chemotherapy-induced metabolic reprogramming in pancreatic cancer promotes anti-tumor immunity and chemo-response.

The molecular dynamics of pancreatic ductal adenocarcinoma (PDAC) under chemotherapy remain incompletely understood. The widespread use of neoadjuvant chemotherapy (NAC) provides a unique opportunity to investigate PDAC samples post-chemotherapy. Leveraging a cohort from Fudan University Shanghai Cancer Center, encompassing PDAC samples with and without exposure to neoadjuvant albumin-bound paclitaxel and gemcitabine (AG), we have compiled data from single-cell and spatial transcriptomes, proteomes, bulk transcriptomes, and metabolomes, deepening our comprehension of the molecular changes in PDACs in response to chemotherapy. Metabolic flux analysis reveals that NAC induces a reprogramming of PDAC metabolic patterns and enhances immunogenicity. Notably, NAC leads to the downregulation of glycolysis and the upregulation of CD36. Tissue microarray analysis demonstrates that high CD36 expression is linked to poorer survival in patients receiving postoperative AG. Targeting CD36 synergistically improves the PDAC response to AG both in vitro and in vivo, including patient-derived preclinical models.

Effects of abnormal expression of CD73 on malignant phenotype of nasopharyngeal carcinoma.

Cluster of differentiation (CD) 73, encoded by the NT5E gene, plays important enzymatic and non-enzymatic roles in cells. There is growing evidence show that CD73 is a key regulator in the development of tumor. Nasopharyngeal carcinoma (NPC) is one of the most common cancers in east and southeast Asia. It is urgent to know more about the mechanism of NPC development and find diagnostic markers for the patients. In this research, we carried out western blot, immunohistochemistry and qRT-PCR to investigate the expression level of CD73 and found that NPC tissues had higher level of CD73 than normal tissues. We also detected the relationship between its expression level with the clinicopathological features and prognosis of NPC patients. The results showed that CD73 expression was related to the clinical stages, lymph node metastasis and survival state of NPC patients. More importantly, patients with higher expression of CD73 had poorer prognosis. Then, CD73 was knocked down in NPC cells (CNE2 and CNE1), and its effects on cell proliferation and migration were investigated by CCK8, colony formation, Transwell and wound-healing assays. We found that knocking down the expression of CD73 in NPC cells could inhibit cells malignant phenotype. Collectively, CD73 plays important roles in NPC malignant behavior and might act as a novel target for the diagnosis and treatment of NPC.

CRIP1 fosters MDSC trafficking and resets tumour microenvironment via facilitating NF-κB/p65 nuclear translocation in pancreatic ductal adenocarcinoma.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is among the most immunosuppressive tumour types. The tumour immune microenvironment (TIME) is largely driven by interactions between immune cells and heterogeneous tumour cells. Here, we aimed to investigate the mechanism of tumour cells in TIME formation and provide potential combination treatment strategies for PDAC patients based on genotypic heterogeneity. DESIGN: Highly multiplexed imaging mass cytometry, RNA sequencing, mass cytometry by time of flight and multiplex immunofluorescence staining were performed to identify the pro-oncogenic proteins associated with low immune activation in PDAC. An in vitro coculture system, an orthotopic PDAC allograft tumour model, flow cytometry and immunohistochemistry were used to explore the biological functions of cysteine-rich intestinal protein 1 (CRIP1) in tumour progression and TIME formation. RNA sequencing, mass spectrometry and chromatin immunoprecipitation were subsequently conducted to investigate the underlying mechanisms of CRIP1. RESULTS: Our results showed that CRIP1 was frequently upregulated in PDAC tissues with low immune activation. Elevated CRIP1 expression induced high levels of myeloid-derived suppressor cell (MDSC) infiltration and fostered an immunosuppressive tumour microenvironment. Mechanistically, we primarily showed that CRIP1 bound to nuclear factor kappa-B (NF-κB)/p65 and facilitated its nuclear translocation in an importin-dependent manner, leading to the transcriptional activation of CXCL1/5. PDAC-derived CXCL1/5 facilitated the chemotactic migration of MDSCs to drive immunosuppression. SX-682, an inhibitor of CXCR1/2, blocked tumour MDSC recruitment and enhanced T-cell activation. The combination of anti-PD-L1 therapy with SX-682 elicited increased CD8+T cell infiltration and potent antitumor activity in tumour-bearing mice with high CRIP1 expression. CONCLUSIONS: The CRIP1/NF-κB/CXCL axis is critical for triggering immune evasion and TIME formation in PDAC. Blockade of this signalling pathway prevents MDSC trafficking and thereby sensitises PDAC to immunotherapy.

Radical antegrade modular pancreatosplenectomy (RAMPS) versus standard retrograde pancreatosplenectomy (SRPS) for resectable body and tail pancreatic adenocarcinoma: protocol of a multicenter, prospective, randomized phase III control trial (CSPAC-3).

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Radical surgical resection offers the only potential cure. There is increasing agreement that radical antegrade modular pancreatosplenectomy (RAMPS) may benefit patients with tumors in the body and tail of the pancreas. To address this, the Chinese Study Group for Pancreatic Cancer (CSPAC)-3 trial is proposed to compare the effect of RAMPS and standard retrograde pancreatosplenectomy (SRPS) on patient survival and preoperative safety METHODS: The randomized controlled trial will be multicenter and two-armed with blinded outcomes and intention-to-treat analysis. Three hundred patients with resectable body and tail pancreatic adenocarcinoma will be enrolled and randomly assigned to RAMPS or SRPS. Adjuvant chemotherapy based on an initial regimen will be recommended 4-6 weeks after surgery if no serious complication occurs. The hypothesis that RAMPS improves survival outcomes compared with SRPS will be tested using a superiority trial. The primary outcome will be overall survival (OS). Secondary outcomes will include recurrence-free survival (RFS), R0 resection rate, the number of harvested lymph nodes, postoperative complications, and quality of life scores. DISCUSSION: The use of RAMPS has increased over the past decade. It is reported that RAMPS is superior to SRPS in improving both the rate of R0 resection and lymph node yield. Despite these advantages, however, there is little high-level documentation of the superiority of RAMPS in terms of survival and this needs to be investigated. To address this issue, CSPAC has instigated the first prospective, randomized phase III control trials, aiming to explore the optimal surgical strategy for improving the prognosis and OS of patients with left-sided pancreatic cancer Trial registration Chinese Clinical Trial Registry ChiCTR2100053844; pre-results. Registered on December 1, 2021.