The advent of immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway has revolutionized cancer treatment, resulting in improved clinical outcomes. However, resistance remains a critical challenge. This study aimed to comparatively elucidate immunophenotypic changes in syngeneic mouse models sensitive (MC-38) or resistant (LLC1) to anti-PD-1 monoclonal antibody (mAb) treatment. In the sensitive MC-38 model, anti-PD-1 therapy increased dendritic cells (DCs) and macrophages, while decreasing myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment. Enhanced expression of antigen presentation molecules (MHC I/II) and costimulatory molecules (CD80/CD86) was observed on tumor-associated DCs and macrophages. Tumor-infiltrating CD4+T, CD8+T, regulatory T, NK, and NKT cells also significantly increased. Importantly, treatment boosted lymphocyte cytotoxic potential, with perforin identified as a key marker of efficacy. Notably, perforin expression in CD4+T and NKT cells strongly negatively correlated with tumor volume. In contrast, the resistant LLC1 model exhibited minimal immunophenotypic changes upon treatment. These findings highlight critical immune modifications induced by anti-PD-1 therapy, particularly the role of perforin, and the DC/MDSC ratio in predicting therapeutic outcomes. This research offers valuable insights into potential predictive biomarkers and informs strategies to overcome resistance, emphasizing the complex interplay between anti-PD-1 treatment and the tumor microenvironment, ultimately aiming to improve immunotherapy response rates.

Pancreatic adenocarcinoma, a malignancy that arises in the cells of the pancreas, is a devastating disease with unclear etiology and often poor prognosis. Locally advanced pancreatic cancer, a stage where the tumor has grown significantly but has not yet spread to distant organs, presents unique challenges in treatment. This article aims to discuss the current strategies, challenges, and future directions in the management of locally advanced pancreatic adenocarcinoma (LAPC).

To investigate the feasibility and efficacy of programmed cell death 1 (PD-1) inhibitor sintilimab plus concurrent chemoradiotherapy for LAPC.

Eligible patients had LAPC, an Eastern cooperative oncology group performance status of 0 or 1, adequate organ and marrow functions, and no prior anticancer therapy. In the observation group, participants received intravenous sintilimab 200 mg once every 3 wk, and received concurrent chemoradiotherapy (concurrent conventional fractionated radiotherapy with doses planning target volume 50.4 Gy and gross tumor volume 60 Gy in 28 fractions and oral S-1 40 mg/m2 twice daily on days 1-14 of a 21-d cycle and intravenous gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-d cycle for eight cycles until disease progression, death, or unacceptable toxicity). In the control group, participants only received concurrent chemoradiotherapy. From April 2020 to November 2021, 64 participants were finally enrolled with 34 in the observation group and 30 in the control group.

Thirty-four patients completed the scheduled course of chemoradiotherapy, while 32 (94.1%) received sintilimab plus concurrent chemoradiotherapy with 2 patients discontinuing sintilimab in the observation group. Thirty patients completed the scheduled course of chemoradiotherapy in the control group. Based on the Response Evaluation Criteria in Solid Tumors guidelines, the analysis of the observation group revealed that a partial response was observed in 11 patients (32.4%), stable disease was evident in 19 patients (55.9%), and 4 patients (11.8%) experienced progressive disease; a partial response was observed in 6 (20.0%) patients, stable disease in 18 (60%), and progressive disease in 6 (20%) in the control group. The major toxic effects were leukopenia and nausea. The incidence of severe adverse events (AEs) (grade 3 or 4) was 26.5% (9/34) in the observation group and 23.3% (7/30) in the control group. There were no treatment-related deaths. The observation group demonstrated a significantly longer median overall survival (22.1 mo compared to 15.8 mo) (P < 0.05) and progression-free survival (12.2 mo vs 10.1 mo) (P < 0.05) in comparison to the control group. The occurrence of severe AEs did not exhibit a statistically significant difference between the observation group and the control group (P > 0.05).

Sintilimab plus concurrent chemoradiotherapy was effective and safe for LAPC patients, and warrants further investigation.

Pancreatic cancer (PC) is a highly malignant tumour of the digestive system with poor therapeutic response and low survival rates. Immunotherapy has rapidly developed in recent years and has achieved significant outcomes in numerous malignant neoplasms. However, responses to immunotherapy in PC are rare, and the immunosuppressive and desmoplastic tumour microenvironment (TME) significantly hinders their efficacy in PC. Tumour-associated neutrophils (TANs) play a crucial role in the PC microenvironment and exert a profound influence on PC immunotherapy by establishing a robust stromal shelter and restraining immune cells to assist PC cells in immune escape, which may subvert the current status of PC immunotherapy. The present review aims to offer a comprehensive summary of the latest progress in understanding the involvement of TANs in PC desmoplastic and immunosuppressive functions and to emphasise the potential therapeutic implications of focusing on TANs in the immunotherapy of this deleterious disease. Finally, we provide an outlook for the future use of TANs in PC immunotherapy.

Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as KRAS, TP53, and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.

Pancreatic ductal adenocarcinoma remains associated with a poor prognosis, even when diagnosed at an early stage. Consequently, it is imperative to carefully consider the available therapeutic options and tailor them based on clinically relevant biomarkers. In our comprehensive review, we specifically concentrated on the identification of novel predictive and prognostic markers that have the potential to be integrated into multiparametric scoring systems. These scoring systems aim to accurately predict the efficacy of neoadjuvant chemotherapy in surgically resectable pancreatic cancer cases. By identifying robust predictive markers, we can enhance our ability to select patients who are most likely to benefit from neoadjuvant chemotherapy. Furthermore, the identification of prognostic markers can provide valuable insights into the overall disease trajectory and inform treatment decisions. The development of multiparametric scoring systems that incorporate these markers holds great promise for optimizing the selection of patients for neoadjuvant chemotherapy, leading to improved outcomes in resectable pancreatic neoplasia. Continued research efforts are needed to validate and refine these markers and scoring systems, ultimately advancing the field of personalized medicine in pancreatic adenocarcinoma management.

Pexidartinib, a macrophage colony-stimulating factor receptor (CSF-1R) inhibitor, is indicated for the treatment of tendon sheath giant cell tumor (TGCT). However, few studies on the toxicity mechanisms of pexidartinib for embryonic development. In this study, the effects of pexidartinib on embryonic development and immunotoxicity in zebrafish were investigated. Zebrafish embryos at 6 h post fertilization (6 hpf) were exposed to 0, 0.5, 1.0, and 1.5 μM concentrations of pexidartinib, respectively. The results showed that different concentrations of pexidartinib induced the shorter body, decreased heart rate, reduced number of immune cells and increase of apoptotic cells. In addition, we also detected the expression of Wnt signaling pathway and inflammation-related genes, and found that these genes expression were significantly upregulated after pexidartinib treatment. To test the effects of embryonic development and immunotoxicity due to hyperactivation of Wnt signaling after pexidartinib treatment, we used IWR-1, Wnt inhibitor, for rescue. Results show that IWR-1 could not only rescue developmental defects and immune cell number, but also downregulate the high expression of Wnt signaling pathway and inflammation-related caused by pexidartinib. Collectively, our results suggest that pexidartinib induces the developmental toxicity and immunotoxicity in zebrafish embryos through hyperactivation of Wnt signaling, providing a certain reference for the new mechanisms of pexidartinib function.

Pancreatic intraductal papillary mucinous neoplasms (IPMNs) have gained substantial attention because they represent one of the only radiographically identifiable precursors of invasive pancreatic ductal adenocarcinoma. Although most of these neoplasms have low-grade dysplasia and will remain indolent, a subset of IPMNs will progress to invasive cancer. The role of the immune system in the progression of IPMNs is unclear, but understanding its role could reveal the mechanism of neoplastic progression and targets for immunotherapy to inhibit progression or treat invasive disease. The available evidence supports a shift in the immune composition of IPMNs during neoplastic progression. Although low-grade lesions contain a high proportion of effector T cells, high-grade IPMNs, and IPMNs with an associated invasive carcinoma lose the T-cell infiltrate and are characterised by a predominance of immunosuppressive elements. Several possible therapeutic strategies emerge from this analysis that are unique to IPMNs and its microbiome.

Pancreatic cancer is a digestive system malignancy and poses a high mortality worldwide. Traditionally, neutrophils have been thought to play a role in acute inflammation. In contrast, their importance during tumor diseases has been less well studied. Generally, neutrophils are recruited into the tumor microenvironment and exert inflammation and tumor-promoting effects. As an essential part of the tumor microenvironment, neutrophils play diverse roles in pancreatic cancer, such as angiogenesis, progression, metastasis and immunosuppression. Additionally, neutrophils can be a new potential therapeutic target in cancer. Inhibitors of cytokines, chemokines and neutrophil extracellular traps can exert antitumor effects. In this review, we describe the role of neutrophils in the development and progression of pancreatic cancer, discuss their potential as therapeutic targets, and aim to provide ideas for improving the prognosis of patients with this malignant tumor disease.