BACKGROUND: Although immune checkpoint blockade (ICB) therapy has proven to be extremely effective at managing certain cancers, its efficacy in treating pancreatic ductal adenocarcinoma (PDAC) has been limited. Therefore, enhancing the effect of ICB could improve the prognosis of PDAC. In this study, we focused on the histamine receptor H1 (HRH1) and investigated its impact on ICB therapy for PDAC. METHODS: We assessed HRH1 expression in pancreatic cancer cell (PCC) specimens from PDAC patients through public data analysis and immunohistochemical (IHC) staining. The impact of HRH1 in PCCs was evaluated using HRH1 antagonists and small hairpin RNA (shRNA). Techniques including Western blot, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-PCR), and microarray analyses were performed to identify the relationships between HRH1 and major histocompatibility complex class I (MHC-I) expression in cancer cells. We combined HRH1 antagonism or knockdown with anti-programmed death receptor 1 (αPD-1) therapy in orthotopic models, employing IHC, immunofluorescence, and hematoxylin and eosin staining for assessment. RESULTS: HRH1 expression in cancer cells was negatively correlated with HLA-ABC expression, CD8+ T cells, and cytotoxic CD8+ T cells. Our findings indicate that HRH1 blockade upregulates MHC-I expression in PCCs via cholesterol biosynthesis signaling. In the orthotopic model, the combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8+ T cell penetration and efficacy, overcoming resistance to ICB therapy. CONCLUSIONS: HRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy.
Immune Checkpoint Inhibitors , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/genetics , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Mice , Animals , Receptors, Histamine H1/metabolism , Receptors, Histamine H1/genetics , Histocompatibility Antigens Class I/metabolism , Histocompatibility Antigens Class I/genetics , Cell Line, Tumor , Female , Histamine H1 Antagonists/pharmacology , Histamine H1 Antagonists/therapeutic use , Male
Intratumor bacteria modify the tumor immune microenvironment and influence outcomes of various tumors. Periodontal pathogen Fusobacterium nucleatum has been detected in pancreatic cancer tissues and is associated with poor prognosis. However, it remains unclear how F. nucleatum affects pancreatic cancer. Here, we compared clinical features with F. nucleatum colonization in pancreatic cancer tissues. F. nucleatum was detected in 15.5% (13/84) of pancreatic cancer patients. The tumor size was significantly larger in the F. nucleatum-positive group than in the negative group. To clarify the biological effect of intratumor F. nucleatum on pancreatic cancer progression, we performed migration/invasion assays and cytokine array analysis of cancer cells cocultured with F. nucleatum. F. nucleatum promoted CXCL1 secretion from pancreatic cancer cells, leading to cancer progression through autocrine signaling. Intratumor F. nucleatum suppressed tumor-infiltrating CD8+ T cells by recruiting myeloid-derived suppressor cells (MDSCs) to the tumor in an F. nucleatum-injected subcutaneous pancreatic cancer mouse model, resulting in tumor progression. Furthermore, tumor growth accelerated by F. nucleatum was suppressed by MDSC depletion or cytokine inhibitors. Intratumor F. nucleatum promoted pancreatic cancer progression through autocrine and paracrine mechanisms of the CXCL1-CXCR2 axis. Blockade of the CXCL1-CXCR2 axis may be a novel therapeutic approach for patients with intratumor F. nucleatum-positive pancreatic cancer.
Colorectal Neoplasms , Pancreatic Neoplasms , Animals , Mice , Fusobacterium nucleatum , CD8-Positive T-Lymphocytes/pathology , Colorectal Neoplasms/pathology , Cytokines , Tumor Microenvironment , Pancreatic Neoplasms
OBJECTIVES: Non-surgical treatment is an acceptable approach for managing appendiceal abscess in adults. However, it is only applicable for selected patients, and conversion to surgery is mandatory for failed conservative treatment. This study aimed to determine the predictive factors for unsuccessful outcomes. METHODS: Of 594 patients with acute appendicitis, 34 (5.7%) diagnosed with appendiceal abscess were initially treated conservatively. Patients were divided into two groups: the conservative group, which was successfully treated with antibiotics and percutaneous abscess drainage, and the conversion group, which comprised patients who had surgical conversion despite conservative treatment. Risk factors for the conversion group were investigated by comparing clinical and radiological parameters between the two groups. RESULTS: Eight (23.4%) patients were converted to surgical management at an average of 5.5 days of non-surgical treatment. An abscess size greater than 40 mm and a lower rate of improvement in the white blood cell (WBC) count were significant factors for predicting conversion in multivariate analysis. The conversion group had a long operative time and high morbidity and operative conversion rates (change of proposed initial operation). Early conversion to operation group, i.e., less than 5 days of treatment, contributed to a significantly shorter hospital stay, lower hospital cost, and relatively shorter operative time (p = 0.02, p = 0.04, and p = 0.11, respectively). CONCLUSIONS: Contributing factors in predicting unsuccessful outcomes for non-surgical treatment include an abscess size greater than 40 mm and a low rate of improvement in WBC count on the first day of antibiotic treatment.
