Immunotherapy Pancreatic

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy worldwide owing to its complex tumour microenvironment and dense physical barriers. Stromal-derived factor-1 (SDF-1), which is abundantly secreted by tumour stromal cells, plays a pivotal role in promoting PDAC growth and metastasis. In this study, we investigated the impact and molecular mechanisms of the anti-PD-L1&CXCR4 bispecific nanobody on the TME and their consequent interference with PDAC progression. We found that blocking the SDF-1/CXCR4 signalling pathway delayed the epithelial-mesenchymal transition in pancreatic cancer cells...

We report a distinctive case of malignant oncocytic carcinoma originating in the pancreas, an organ rarely associated with such tumours. We discuss the diagnostic journey, highlighting the tumour's resemblance to renal cell carcinoma but without renal involvement. A significant aspect of this case is the successful and sustained response to combined immunotherapy and tyrosine kinase inhibitors, demonstrating a potential therapeutic pathway for similar rare cases. This study contributes to a deeper understanding of pancreatic oncocytic tumours and their management...

BACKGROUND: Pancreatic, periampullary/ampullary, and choledochal adenocarcinomas are aggressive malignancies with a poor prognosis. Immune checkpoint blockade is a promising treatment option for several tumor types. H long terminal repeat-associating 2 (HHLA2), which is analogous to programmed death-ligand 1 (PD-L1), is a recently discovered member of the B7/cluster of differentiation 28 family and is expressed in many malignancies. AIM: To analyze the expression of HHLA2 and its association with the pathologic biomarkers that predict sensitivity to immunotherapy...

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with limited effective treatment especially after first-line chemotherapy. The human epidermal growth factor receptor 2 (HER-2) immunohistochemistry (IHC) positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC. CASE SUMMARY: We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn't have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment...

The immunosuppressive microenvironment caused by several intrinsic and extrinsic mechanism has brought great challenges to the immunotherapy of pancreatic cancer. We identified GFPT2, the key enzyme in hexosamine biosynthesis pathway (HBP), as an immune-related prognostic gene in pancreatic cancer using transcriptome sequencing and further confirmed that GFPT2 promoted macrophage M2 polarization and malignant phenotype of pancreatic cancer. HBP is a glucose metabolism pathway leading to the generation of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which is further utilized for protein O-GlcNAcylation...

Substantial progress has been made toward understanding biology and developing new therapies for pancreatic ductal adenocarcinoma (PDAC). In this review, new insights from genomic profiling, as well as implications for treatment and prognosis, are discussed. New standards of care approaches with a focus on drug therapies are discussed for the treatment of resectable and advanced PDAC. The role of targeted and immune therapies remains limited; cohorts likely to benefit from these approaches are discussed. Promising, preliminary results regarding experimental therapies are reviewed...

The role of PIWI-interacting RNAs (piRNAs) in small extracellular vesicles (sEV) derived from pancreatic neuroendocrine neoplasms (PNEN) in the tumor microenvironment (TME) remains unexplored. We used multiplex immunohistochemistry (mIHC) to analyze the expression of CD68, CD276 (B7H3) and CD3 on PNEN. CD276+ tumor-associated macrophages (TAMs) were more abundant in tumor tissues than nontumor tissues and negatively correlated with T-cell infiltration. Serum sEV piRNA sequencing was performed to identify piRNAs enriched in PNEN patients...

Background: Pancreatic adenocarcinoma (PAAD) is a highly malignant gastrointestinal tumor and is associated with an unfavorable prognosis worldwide. Considering the effect of mitochondrial metabolism on the prognosis of pancreatic cancer has rarely been investigated, we aimed to establish prognostic gene markers associated with mitochondrial energy metabolism for the prediction of survival probability in patients with PAAD. Methods: Gene expression data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases, and the mitochondrial energy metabolism-related genes were obtained from the GeneCards database...

BACKGROUND: Less than 10% of people who have pancreatic ductal adenocarcinoma (PDAC) will survive the malignancy for five years. The ion channel genes-related biomarker and predictive model were needed for exploitation. METHODS: Differentially expressed ion channel genes (DEICGs) were detected in PDAC patients. GO and KEGG enrichment analysis was conducted on DEICGs. The prognostic genes were found using Cox regression analysis. After that, a risk model was created and examined...

The MYC proto-oncogenes (c-MYC, MYCN , MYCL ) are among the most deregulated oncogenic drivers in human malignancies including high-risk neuroblastoma, 50% of which are MYCN -amplified. Genetically engineered mouse models (GEMMs) based on the MYCN transgene have greatly expanded the understanding of neuroblastoma biology and are powerful tools for testing new therapies. However, a lack of c-MYC-driven GEMMs has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and therapy development given that c-MYC is also an important driver of many high-risk neuroblastomas...

INTRODUCTION: Fibroblast activation protein (FAP) is predominantly upregulated in various tumor microenvironments and scarcely expressed in normal tissues. METHODS: We analyzed FAP across 1216 tissue samples covering 23 tumor types and 70 subtypes. RESULTS: Elevated FAP levels were notable in breast, pancreatic, esophageal, and lung cancers. Using immunohistochemistry and RNAseq, a correlation between FAP gene and protein expression was found...

BACKGROUND: Claudin 18.2 (CLDN18.2) is a highly anticipated target for solid tumor therapy, especially in advanced gastric carcinoma and pancreatic carcinoma. The T cell engager targeting CLDN18.2 represents a compelling strategy for enhancing anti-cancer efficacy. METHODS: Based on the in-house screened anti-CLDN18.2 VHH, we have developed a novel tri-specific T cell engager targeting CLDN18.2 for gastric and pancreatic cancer immunotherapy. This tri-specific antibody was designed with binding to CLDN18...

OBJECTIVE: To construct a prognostic model based on MR features and clinical data to evaluate the progression free survival (PFS), overall survival (OS) and objective response rate (ORR) of pancreatic cancer patients with hepatic metastases who received chemoimmunotherapy. METHODS: 105 pancreatic cancer patients with hepatic metastases who received chemoimmunotherapy were assigned to the training set (n = 52), validation set (n = 22), and testing set (n = 31)...

This study aims to investigate the diagnostic potential of IL-2 for PDAC and develop a method to improve the dendritic cell (DC) based vaccine against PDAC. The gene expression data and clinical characteristics information for 178 patients with PDAC were obtained from The Cancer Genome Atlas (TCGA). DCs were isolated from Human peripheral blood mononuclear cells (PBMCs) and were cultured in 4 different conditions. DCs were pulsed by tumor cell lysates or KRAS G12D1 - 23 peptide, and then used to activate T cells...

Approximately 90% of pancreatic cancer (PC) contain KRAS mutations. Mutated KRAS activates the downstream oncogenic PI3K/AKT and MEK signaling pathways and induces drug resistance. However, targeting both pathways with different drugs can also lead to excessive toxicity. ONC201 is a dual PI3K/AKT and MEK pathway inhibitor with an excellent safety profile that targets death receptor 5 (DR5) to induce apoptosis. Gemcitabine (GEM) is a first-line chemotherapy in PC, but it is metabolically unstable and can be stabilized by a prodrug approach...

BACKGROUND: In the second-line treatment of advanced pancreatic cancer (APC), there is only one approved regimen based on the phase III NAPOLI-1 trial. However, for patients progressing after Nab-paclitaxel and Gemcitabine (Nab-P/Gem) or Nab-P combinations, second-line treatment were very limited. METHODS: This is a retrospective single-center analysis of patients. Our aim was to determine the effectiveness and tolerability of a novel regimen, gemcitabine plus Anlotinib and anti-PD1, in APC patients and to compare it with oxaliplatin, irinotecan, leucovorin, and fluorouracil (FOLFIRINOX) in the second-line setting who have failed on the first-line Nab-P combinations...

CD8+ T cells affect the outcomes of pancreatic ductal adenocarcinoma (PDAC). Using tissue samples at pre-treatment to monitor the immune response is challenging, while blood samples are beneficial in overcoming this limitation. In this study, we measured peripheral antigen-specific CD8+ T cell responses against four different tumor-associated antigens (TAAs) in PDAC using flow cytometry and investigated their relationships with clinical features. We analyzed the optimal timing within the treatment course for effective immune checkpoint inhibition in vitro ...

Malignant tumors are often associated with an immunosuppressive tumor microenvironment (TME), rendering most of them resistant to standard-of-care immune checkpoint inhibitors (CPIs). Signal transducer and activator of transcription 3 (STAT3), a ubiquitously expressed transcription factor, has well-defined immunosuppressive functions in several leukocyte populations within the TME. Since the STAT3 protein has been challenging to target using conventional pharmaceutical modalities, we investigated the feasibility of applying systemically delivered RNA interference (RNAi) agents to silence its mRNA directly in tumor-associated immune cells...

The treatment of digestive system tumors presents challenges, particularly in immunotherapy, owing to the advanced immune tolerance of the digestive system. Nanomaterials have emerged as a promising approach for addressing these challenges. They provide targeted drug delivery, enhanced permeability, high bioavailability, and low toxicity. Additionally, nanomaterials target immunosuppressive cells and reshape the tumor immune microenvironment (TIME). Among the various cells in the TIME, tumor-associated macrophages (TAMs) are the most abundant and play a crucial role in tumor progression...

Pancreatic cancer is a lethal disease, harboring a five-year overall survival rate of only 13%. Current treatment approaches thus require modulation, with attention shifting towards liberating the stalled efficacy of immunotherapies. Select chemotherapy drugs which possess inherent immune-modifying behaviors could revitalize immune activity against pancreatic tumors and potentiate immunotherapeutic success. In this study, we characterized the influence of gemcitabine, a chemotherapy drug approved for the treatment of pancreatic cancer, on tumor antigen presentation by human leukocyte antigen class I (HLA-I)...