Immunotherapy For Pancreatic Cancer Research Articles

Tertiary lymphoid structures in pancreatic cancer: a new target for immunotherapy.

Pancreatic cancer (PC) is extremely malignant and shows limited response to available immunotherapies due to the hypoxic and immunosuppressive nature of its tumor microenvironment (TME). The aggregation of immune cells (B cells, T cells, dendritic cells, etc.), which is induced in various chronic inflammatory settings such as infection, inflammation, and tumors, is known as the tertiary lymphoid structure (TLS). Several studies have shown that TLSs can be found in both intra- and peritumor tissues of PC. The role of TLSs in peritumor tissues in tumors remains unclear, though intratumoral TLSs are known to play an active role in a variety of tumors, including PC. The formation of intratumoral TLSs in PC is associated with a good prognosis. In addition, TLSs can be used as an indicator to assess the effectiveness of treatment. Targeted induction of TLS formation may become a new avenue of immunotherapy for PC. This review summarizes the formation, characteristics, relevant clinical outcomes, and clinical applications of TLSs in the pancreatic TME. We aim to provide new ideas for future immunotherapy of PC.

Analysis of M2 macrophage-associated risk score signature in pancreatic cancer TME landscape and immunotherapy.

Background: M2 macrophages perform an influential role in the progression of pancreatic cancer. This study is dedicated to explore the value of M2 macrophage-related genes in the treatment and prognosis of pancreatic cancer. Methods: RNA-Seq and clinical information were downloaded from TCGA, GEO and ICGC databases. The pancreatic cancer tumour microenvironment was revealed using the CIBERSORT algorithm. Weighted gene co-expression network analysis (WGCNA) was used to detect M2 macrophage-associated gene modules. Univariate Cox regression, Least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate Cox regression were applied to develop the prognostic model. The modelling and validation cohorts were divided into high-risk and low-risk groups according to the median risk score. The nomogram predicting survival was constructed based on risk scores. Correlations between risk scores and tumour mutational load, clinical variables, immune checkpoint blockade, and immune cells were further explored. Finally, potential associations between different risk models and chemotherapeutic agent efficacy were predicted. Results: The intersection of the WGCNA results from the TCGA and GEO data screened for 317 M2 macrophage-associated genes. Nine genes were identified by multivariate COX regression analysis and applied to the construction of risk models. The results of GSEA analysis revealed that most of these genes were related to signaling, cytokine receptor interaction and immunodeficiency pathways. The high and low risk groups were closely associated with tumour mutational burden, immune checkpoint blockade related genes, and immune cells. The maximum inhibitory concentrations of metformin, paclitaxel, and rufatinib lapatinib were significantly differences on the two risk groups. Conclusion: WGCNA-based analysis of M2 macrophage-associated genes can help predict the prognosis of pancreatic cancer patients and may provide new options for immunotherapy of pancreatic cancer.

A T Cell-Engaging Tumor Organoid Platform for Pancreatic Cancer Immunotherapy.

Pancreatic ductal adenocarcinoma (PDA) is a clinically challenging disease with limited treatment options. Despite a small percentage of cases with defective mismatch DNA repair (dMMR), PDA is included in the most immune-resistant cancer types that are poorly responsive to immune checkpoint blockade (ICB) therapy. To facilitate drug discovery combating this immunosuppressive tumor type, a high-throughput drug screen platform is established with the newly developed T cell-incorporated pancreatic tumor organoid model. Tumor-specific T cells are included in the pancreatic tumor organoids by two-step cell packaging, fully recapitulating immune infiltration in the immunosuppressive tumor microenvironment (TME). The organoids are generated with key components in the original tumor, including epithelial, vascular endothelial, fibroblast and macrophage cells, and then packaged with T cells into their outside layer mimicking a physical barrier and enabling T cell infiltration and cytotoxicity studies. In the PDA organoid-based screen, epigenetic inhibitors ITF2357 and I-BET151 are identified, which in combination with anti-PD-1 based therapy show considerably greater anti-tumor effect. The combinatorial treatment turns the TME from immunosuppressive to immunoactive, up-regulates the MHC-I antigen processing and presentation, and enhances the effector T cell activity. The standardized PDA organoid model has shown great promise to accelerate drug discovery for the immunosuppressive cancer.

RETRACTED ARTICLE: ITGA3 acts as a purity-independent biomarker of both immunotherapy and chemotherapy resistance in pancreatic cancer: bioinformatics and experimental analysis

Contribution of integrin superfamily genes to treatment resistance remains uncertain. Genome patterns of thirty integrin superfamily genes were analyzed of using bulk and single-cell RNA sequencing, mutation, copy number, methylation, clinical information, immune cell infiltration, and drug sensitivity data. To select the integrins that are most strongly associated with treatment resistance in pancreatic cancer, a purity-independent RNA regulation network including integrins were constructed using machine learning. The integrin superfamily genes exhibit extensive dysregulated expression, genome alterations, epigenetic modifications, immune cell infiltration, and drug sensitivity, as evidenced by multi-omics data. However, their heterogeneity varies among different cancers. After constructing a three-gene (TMEM80, EIF4EBP1, and ITGA3) purity-independent Cox regression model using machine learning, ITGA3 was identified as a critical integrin subunit gene in pancreatic cancer. ITGA3 is involved in the molecular transformation from the classical to the basal subtype in pancreatic cancer. Elevated ITGA3 expression correlated with a malignant phenotype characterized by higher PD-L1 expression and reduced CD8+ T cell infiltration, resulting in unfavorable outcomes in patients receiving either chemotherapy or immunotherapy. Our findings suggest that ITGA3 is an important integrin in pancreatic cancer, contributing to chemotherapy resistance and immune checkpoint blockade therapy resistance.Graphical abstract

The DEAD-box RNA helicase, DDX60, Suppresses immunotherapy and promotes malignant progression of pancreatic cancer

Excessive proliferation, invasion, metastasis, and immune resistance in pancreatic cancer (PC) makes it one of the most lethal malignant tumors. Recently, DDX60 was found to be involved in the development of various tumors and in immunotherapy. Therefore, we aimed to investigate whether DDX60 is a new factor involved in PC immunotherapy. The DDX60 mRNA was screened using transcriptome sequencing (RNA-seq). The Cox and survival analysis of DDX60 was performed using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. In addition, clinical and immune infiltration data in the databases were analyzed and plotted using the R language. Clinical samples and in vitro experiments were used to determine the molecular evolution of DDX60 during PC progression. We found that DDX60 was upregulated in PC tissues (P value = 0.0083) and was associated with poor prognosis and short survival time of patients with PC. Results of Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set variation analyses showed that viral defense, tumor, and immune-related pathways were significantly enriched in samples with high DDX60 expression. The Pearson correlation test demonstrated that DDX60 expression correlated strongly with immune checkpoint and immune system-related metagene clusters. Our results indicated that DDX60 promoted cell proliferation, migration, and invasion and was related to poor prognosis and immune resistance. Therefore, DDX60 may be a promising novel target for PC immunotherapy.

T cells in pancreatic cancer stroma: Tryptophan metabolism plays an important role in immunoregulation.

Several studies have shown that the immune system is highly regulated by tryptophan metabolism, which serves as an immunomodulatory factor. The indoleamine 2,3-dioxygenase 1 (IDO1), as an intracellular enzyme that participates in metabolism of the essential amino acid tryptophan in the kynurenine pathway, is an independent prognostic marker for pancreatic cancer (PC). First, overexpression of IDO1 inhibits the maturation of dendritic cells and T-cell proliferation in the liver and spleen. Second, the high expression of kynurenine induces and activates the aryl hydrocarbon receptor, resulting in upregulated programmed cell death protein 1 expression. Third, the induction of IDO1 can lead to loss of the T helper 17 cell/regulatory T cell balance, mediated by the proximal tryptophan catabolite from IDO metabolism. In our study, we found that overexpression of IDO1 upregulated CD8+ T cells and reduced natural killer T cells in pancreatic carcinoma in mice. Hence, it may be essential to pay more attention to tryptophan metabolism in patients, especially those who are tolerant to immunotherapy for PC.

Targeting tumor immunosuppressive microenvironment for pancreatic cancer immunotherapy: Current research and future perspective.

Pancreatic cancer is one of the most malignant tumors with increased incidence rate. The effect of surgery combined with chemoradiotherapy on survival of patients is unsatisfactory. New treatment strategy such as immunotherapy need to be investigated. The accumulation of desmoplastic stroma, infiltration of immunosuppressive cells including myeloid derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs), as well as tumor associated cytokine such as TGF-β, IL-10, IL-35, CCL5 and CXCL12 construct an immunosuppressive microenvironment of pancreatic cancer, which presents challenges for immunotherapy. In this review article, we explore the roles and mechanism of immunosuppressive cells and lymphocytes in establishing an immunosuppressive tumor microenvironment in pancreatic cancer. In addition, immunotherapy strategies for pancreatic cancer based on tumor microenvironment including immune checkpoint inhibitors, targeting extracellular matrix (ECM), interfering with stromal cells or cytokines in TME, cancer vaccines and extracellular vesicles (EVs) are also discussed. It is necessary to identify an approach of immunotherapy in combination with other modalities to produce a synergistic effect with increased response rates in pancreatic cancer therapy.

Targeting ZDHHC9 potentiates anti-programmed death-ligand 1 immunotherapy of pancreatic cancer by modifying the tumor microenvironment

Immune checkpoint blockade (ICB) therapy targeting the programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) axis has achieved considerable success in treating a wide range of cancers. However, most patients with pancreatic cancer remain resistant to ICB. Moreover, there is a lack of optimal biomarkers for the prediction of response to this therapy. Palmitoylation is mediated by a family of 23 S-acyltransferases, termed zinc finger Asp‐His‐His‐Cys-type palmitoyltransferases (ZDHHC), which precisely control various cancer-related protein functions and represent promising drug targets for cancer therapy. Here, we revealed that tumor cell-intrinsic ZDHHC9 was overexpressed in pancreatic cancer tissues and associated with impaired anti-tumor immunity. In syngeneic pancreatic tumor models, the knockdown of ZDHHC9 expression suppressed tumor progression and prolonged survival time of mice by modifying the immunosuppressive (‘cold’) to proinflammatory (‘hot’) tumor microenvironment. Furthermore, ZDHHC9 deficiency sensitized anti-PD-L1 immunotherapy mainly in a CD8+ T cell dependent manner. Lastly, we employed the ZDHHC9-siRNA nanoparticle system to efficiently silence ZDHHC9 in pancreatic tumors. Collectively, our findings indicate that ZDHHC9 overexpression in pancreatic tumors is a mechanism involved in the inhibition of host anti-tumor immunity and highlight the importance of inactivating ZDHHC9 as an effective immunotherapeutic strategy and booster for anti-PD-L1 therapy against pancreatic cancer.

Identification of m6A/m5C/m1A-associated LncRNAs for prognostic assessment and immunotherapy in pancreatic cancer

Methylation of RNA plays an important role in cancer. Classical forms of such modifications include N6-methyladenine (m6A), 5-methylcytosine (m5C), and N1-methyladenine (m1A). Methylation-regulated long non-coding (lnc) RNAs are involved in various biological processes, such as tumor proliferation, apoptosis, immune escape, invasion, and metastasis. Therefore, we performed an analysis of transcriptomic and clinical data of pancreatic cancer samples in The Cancer Genome Atlas (TCGA). Using the co-expression method, we summarized 44 m6A/m5C/m1A-related genes and obtained 218 methylation-associated lncRNAs. Next, with COX regression, we screened 39 lncRNAs that are strongly associated with prognosis and found that their expression differed significantly between normal tissues and pancreatic cancer samples (P < 0.001). We then used the least absolute shrinkage and selection operator (LASSO) to construct a risk model comprising seven lncRNAs. In validation set, the nomogram generated by combining clinical characteristics accurately predicted the survival probability of pancreatic cancer patients at 1, 2, and 3 years after diagnosis (AUC = 0.652, 0.686, and 0.740, respectively). Tumor microenvironment analysis showed that the high-risk group had significantly more resting memory CD4 T cells, M0 macrophages, and activated dendritic cells and fewer naïve B cells, plasma cells, and CD8 T cells than the low-risk group (both P < 0.05). Most immune-checkpoint genes were significantly different between the high- and low-risk groups (P < 0.05). The Tumor Immune Dysfunction and Exclusion score showed that high-risk patients benefited more from treatment with immune checkpoint inhibitors (P < 0.001). Overall survival was also lower in high-risk patients with more tumor mutations than in low-risk patients with fewer mutations (P < 0.001). Finally, we explored the sensitivity of the high- and low-risk groups to seven candidate drugs. Our findings indicated that m6A/m5C/m1A-associated lncRNAs are potentially useful biomarkers for the early diagnosis and estimating the prognosis of, and ascertaining the responses to immunotherapy in, patients with pancreatic cancer.

Sustained Intratumoral Administration of Agonist CD40 Antibody Overcomes Immunosuppressive Tumor Microenvironment in Pancreatic Cancer (Adv. Sci. 9/2023)

Intratumoral Immunotherapy for Pancreatic Cancer In article number 2206873, Hsuan-Chen Liu, Corrine Ying Xuan Chua, Alessandro Grattoni, and co-workers leveraged a nanofluidic implant to demonstrate the efficacy of sustained intratumoral CD40Ab immunotherapy against pancreatic adenocarcinoma. The intratumoral strategy transformed the tumor immune microenvironment to a phenotype conducive to tumor elimination without systemic toxicity and achieved abscopal response against distant untreated tumors.

ENO1 promotes immunosuppression and tumor growth in pancreatic cancer.

Pancreatic adenocarcinoma (PAAD) is a highly aggressive and malignant cancer type with the highest mortality rate of all major cancers. However, the molecular and tumor immune escape mechanism underlying pancreatic cancer remains largely unclear. α-enolase (ENO1) is a glycolytic enzyme reported to overexpress in a variety of cancer types. This study was undertaken to investigate the functional role and therapeutic potential of ENO1 in pancreatic cancer. We examined the expression levels of ENO1 across a broad spectrum of cancer types from the TCGA database. ENO1-knockout (ENO1-KO) through CRISPR/CAS9 technology in a mouse pancreatic cancer cell line (PAN02) was used to analyze the role of ENO1 on proliferation and colony formation. Flow cytometry and RT-PCR were also applied to analyze T lymphocytes and relevant cytokines. In the present study, we identified that ENO1 promoted pancreatic cancer cell proliferation. Our bioinformatics data indicated that ENO1 was significantly overexpressed in pancreatic cancer cell lines and tissues. Survival analyses revealed that ENO1 overexpression implicated poor survival of PAAD patients. Knockout of ENO1 expression repressed the ability of proliferation and colony formation in PAN02. In addition, ENO1-KO significantly decreased tumor growth in mouse models. Further flow cytometry and RT-PCR analysis revealed that ENO1-KO modulates the tumor microenvironment (TME), especially in suppressed Treg cells and inducing anti-tumor cytokine responses. Taken together, our data showed that ENO1 was an oncogenic biomarker and might serve as a promising target for immunotherapy of pancreatic cancer.

Characterization of neuroendocrine regulation- and metabolism-associated molecular features and prognostic indicators with aid to clinical chemotherapy and immunotherapy of patients with pancreatic cancer.

The worldwide prevalence of pancreatic cancer has been rising in recent decades, and its prognosis has not improved much. The imbalance of substance and energy metabolism in tumour cells is among the primary causes of tumour formation and occurrence, which is often controlled by the neuroendocrine system. We applied Cox and LASSO regression analysis to develop a neuroendocrine regulation- and metabolism-related prognostic risk score model with three genes (GSK3B, IL18 and VEGFA) for pancreatic cancer. TCGA dataset served as the training and internal validation sets, and GSE28735, GSE62452 and GSE57495 were designated as external validation sets. Patients classified as the low-risk population (category, group) exhibited considerably improved survival duration in contrast with those classified as the high-risk population, as determined by the Kaplan-Meier curve. Then, we combined all the samples, and divided them into three clusters using unsupervised clustering analysis. Unsupervised clustering, t-distributed stochastic neighbor embedding (t-SNE), and principal component analysis (PCA) were further utilized to demonstrate the reliability of the prognostic model. Moreover, the risk score was shown to independently function as a predictor of pancreatic cancer in both univariate and multivariate Cox regression analyses. The results of gene set enrichment analysis (GSEA) illustrated that the low-risk population was predominantly enriched in immune-associated pathways. "ESTIMATE" algorithm, single-sample GSEA (ssGSEA) and the Tumor Immune Estimation Resource (TIMER) database showed immune infiltration ratings were enhanced in the low-risk category in contrast with the high-risk group. Tumour immune dysfunction and exclusion (TIDE) database predicted that immunotherapy for pancreatic cancer may be more successful in the high-risk than in the low-risk population. Mutation analysis illustrated a positive link between the tumour mutation burden and risk score. Drug sensitivity analysis identified 44 sensitive drugs in the high- and low-risk population. GSK3B expression was negatively correlated with Oxaliplatin, and IL18 expression was negatively correlated with Paclitaxel. Lastly, we analyzed and verified gene expression at RNA and protein levels based on GENPIA platform, HPA database and quantitative real-time PCR. In short, we developed a neuroendocrine regulation- and metabolism-associated prognostic model for pancreatic cancer that takes into account the immunological microenvironment and drug sensitivity.

Bibliometric Analysis of Hotspots and Frontiers of Immunotherapy in Pancreatic Cancer.

Pancreatic cancer is one of the most common malignant neoplasms with an increasing incidence, low rate of early diagnosis, and high degree of malignancy. In recent years, immunotherapy has made remarkable achievements in various cancer types including pancreatic cancer, due to the long-lasting antitumor responses elicited in the human body. Immunotherapy mainly relies on mobilizing the host's natural defense mechanisms to regulate the body state and exert anti-tumor effects. However, no bibliometric research about pancreatic cancer immunotherapy has been reported to date. This study aimed to assess research trends and offer possible new research directions in pancreatic cancer immunotherapy. The articles and reviews related to pancreatic cancer immunotherapy were collected from the Web of Science Core Collection. CiteSpace, VOSviewer, and an online platform, and were used to analyze co-authorship, citation, co-citation, and co-occurrence of terms retrieved from the literature highlighting the scientific advances in pancreatic cancer immunotherapy. We collected 2475 publications and the number of articles was growing year by year. The United States had a strong presence worldwide with the most articles. The most contributing institution was Johns Hopkins University (103 papers). EM Jaffee was the most productive researcher with 43 papers, and L Zheng and RH Vonderheide ranked second and third, with 34 and 29 papers, respectively. All the keywords were grouped into four clusters: "immunotherapy", "clinical treatment study", "tumor immune cell expression", "tumor microenvironment". In the light of promising hotspots, keywords with recent citation bursts can be summarized into four aspects: immune microenvironment, adaptive immunotherapy, immunotherapy combinations, and molecular and gene therapy. In recent decades, immunotherapy showed great promise for many cancer types, so various immunotherapy approaches have been introduced to treat pancreatic cancer. Understanding the mechanisms of immunosuppressive microenvironment, eliminating immune suppression and blocking immune checkpoints, and combining traditional treatments will be hotspots for future research.

Innate immunity in pancreatic cancer: Lineage tracing and function.

Increasingly, patients with gastrointestinal tumors can benefit from immunotherapy, but not patients with pancreatic cancer. While this lack of benefit has been attributed to lower T-cell infiltration in pancreatic cancer, other studies have demonstrated the presence of numerous T cells in pancreatic cancer, suggesting another mechanism for the poor efficacy of immunotherapy. Single-cell RNA sequencing studies on the pancreatic cancer immune microenvironment have demonstrated the predominance of innate immune cells (e.g., macrophages, dendritic cells, mast cells, and innate immune lymphoid cells). Therefore, in-depth research on the source and function of innate immune lymphocytes in pancreatic cancer could guide pancreatic cancer immunotherapy.

胰腺癌免疫治疗的研究进展

胰腺癌免疫治疗的研究进展

Positive Correlation between PMS2 Deficiency and PD-L1 Expression in Pancreatic Cancer

Background: Pancreatic cancer is one of the most lethal types of cancer, and immunotherapy has become a promising remedy with advancements in tumor immunology. However, predicting the clinical response to immunotherapy in pancreatic cancer remains a dilemma for clinicians. Methods: GEPIA database was used to analyze the differential expression of MMR and PD-L1 genes in 33 common cancer types including pancreatic cancer. The expression levels of MMR and PD-L1 genes were downloaded from the GEPIA and GEO databases to analyze the correlation between MMR genes and PD-L1, and the clinicopathological and survival information were downloaded from the TCGA databases to analyze the relationship between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis. Meanwhile, the tumor tissue samples of 41 patients with pancreatic cancer were collected, and the protein expression levels of MMR and PD-L1 were detected by immunohistochemical assay. Furthermore, we analyzed the correlation between MMR and PD-L1, and the correlation between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis of pancreatic cancer patients. Results: Bioinformatics analysis showed that MLH1, MLH3, MSH2, MSH3, and PMS2 were highly expressed in most cancer types including pancreatic cancer (P P = 0.012), clinical stage (I vs II: P = 0.016), MSH2 expression was related to clinical stage (P P = 0.039), and MSH3 expression was related to T stage (P P P = 0.044) were significantly associated with prognosis. GEPIA data also showed that MSH2 expression was related to prognosis (P = 0.008). The correlation analysis revealed that the expressions MSH2, MLH1, PMS2 had strong correlations with PD-L1 both in GEPIA and GEO databases. Real-world data indicated that of the 41 pancreatic cancer patients, 5 cases had MLH1 deletion, 5 cases had MSH2 deletion, 4 cases had PMS2 deletion, and 12 cases had PD-L1 positive expression. Notably, PMS2 deletion was associated with PD-L1 positive expression (P = 0.035). In addition, MLH1 was related to clinical stage (P = 0.033), age (P = 0.048), and MSH2 was related to clinical stage (P = 0.033). However, MLH1 (P = 0.697), MSH2 (P = 0.956), PMS2 (P = 0.341), and PD-L1 (P = 0.734) appeared to have no impact on overall survival among patients with pancreatic cancer. Conclusion: Both bioinformatics and real-world data showed that there were correlation between PMS2 deletion and PD-L1 expression, and correlation between MLH1, MSH2 and clinical stage.

Prognostic-related genes for pancreatic cancer typing and immunotherapy response prediction based on single-cell sequencing data and bulk sequencing data.

Pancreatic cancer is associated with high mortality and is one of the most aggressive of malignancies, but studies have not fully evaluated its molecular subtypes, prognosis and response to immunotherapy of different subtypes. The purpose of this study was to explore the molecular subtypes and the key genes associated with the prognosis of pancreas cancer patients and study the clinical phenotype, prognosis and response to immunotherapy using single-cell seq data and bulk RNA seq data, and data retrieved from GEO and TCGA databases. Single-cell seq data and bioinformatics methods were used in this study. Pancreatic cancer data were retrieved from GEO and TCGA databases, the molecular subtypes of pancreatic cancer were determined using the six cGAS-STING related pathways, and the clinical phenotype, mutation, immunological characteristics and pathways related to pancreatic cancer were evaluated. Pancreatic cancer was classified into 3 molecular subtypes, and survival analysis revealed that patients in Cluster3 (C3) had the worst prognosis, whereas Cluster1 (C1) had the best prognosis. The clinical phenotype and gene mutation were statistically different among the three molecular subtypes. Analysis of immunotherapy response revealed that most immune checkpoint genes were differentially expressed in the three subtypes. A lower risk of immune escape was observed in Cluster1 (C1), indicating higher sensitivity to immunotherapeutic drugs and subjects in this Cluster are more likely to benefit from immunotherapy. The pathways related to pancreatic cancer were differentially enriched among the three subtypes. Five genes, namely SFRP1, GIPR, EMP1, COL17A and CXCL11 were selected to construct a prognostic signature. Single-cell seq data were to classify pancreatic cancer into three molecular subtypes based on differences in clinical phenotype, mutation, immune characteristics and differentially enriched pathways. Five prognosis-related genes were identified for prediction of survival of pancreatic cancer patients and to evaluate the efficacy of immunotherapy in various subtypes.

Targeting ubiquitin-specific protease 8 sensitizes anti-programmed death-ligand 1 immunotherapy of pancreatic cancer

Programmed death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) help tumor cells evade immune surveillance, and are regarded as important targets of anti-tumor immunotherapy. Post-translational modification of PD-L1 has potential value in immunosuppression. Here, we identified that ubiquitin-specific protease 8 (USP8) deubiquitinates PD-L1. Pancreatic cancer tissues exhibited significantly increased USP8 levels compared with those in normal tissues. Clinically, the expression of USP8 showed a significant association with the tumor-node-metastasis stage in multiple patient-derived cohorts of pancreatic cancer. Meanwhile, USP8 deficiency could reduce tumor invasion and migration and tumor size in an immunity-dependent manner, and improve anti-tumor immunogenicity. USP8 inhibitor pretreatment led to reduced tumorigenesis and immunocompetent mice with Usp8 knockdown tumors exhibited extended survival. Moreover, USP8 interacted positively with PD-L1 and upregulated its expression by inhibiting the ubiquitination-regulated proteasome degradation pathway in pancreatic cancer. Combination therapy with a USP8 inhibitor and anti-PD-L1 effectively suppressed pancreatic tumor growth by activation of cytotoxic T-cells and the anti-tumor immunity was mainly dependent on the PD-L1 pathway and CD8 + T cells. Our findings highlight the importance of targeting USP8, which can sensitize PD-L1-targeted pancreatic cancer to immunotherapy and might represent a novel therapeutic strategy to treat patients with pancreatic tumors in the future.

218P A symbiotic relationship between persistent and emerging resistant oligo-clones dictates resistance to immunotherapy in pancreatic cancer

Immunotherapy has had a limited clinical benefit in pancreatic ductal adenocarcinoma (PDAC). In a pre-clinical mouse model of PDAC treated with glucocorticoid-induced TNFR-related protein (GITR) agonist, the tumours showed nondurable and heterogeneous responses to the GITR agonist. We hypothesised that resistance to GITR agonist is associated with a unique symbiotic interaction between persistent and emergent tumour clones resistant to therapy response.

Progress and prospects for use of cellular immunotherapy in pancreatic cancer.

Pancreatic cancer (PC) is a highly malignant tumor with an increasing incidence rate in recent years. Because pancreatic cancer has an insidious onset, unknown pathophysiology, and poor prognosis, the overall survival rate of pancreatic cancer patients has not improved considerably even with extensive treatment methods such as surgery, radiation, biotherapy, and targeted therapy. Therefore, finding and developing more effective and safe treatments for pancreatic cancer is critical. Cellular immunotherapy has achieved considerable advances in the field of oncology in recent years. Technology is continuously advancing, with new breakthroughs virtually every month, and pancreatic cancer eradication is expected to improve considerably. This article examines the advance of chimeric antigen receptor NK cell immunotherapy (CAR-NK) cell immunotherapy for pancreatic cancer research, as well as research ideas for pancreatic cancer treatment.