Immunotherapy For Pancreatic Cancer Research Articles

Increased Expression of Mitochondrial UQCRC1 in Pancreatic Cancer Impairs Antitumor Immunity of Natural Killer Cells via Elevating Extracellular ATP.

Pancreatic cancer (PC) is one of the most lethal malignancies characterized by a highly immunosuppressive tumor microenvironment (TME). Previously, we have reported that ubiquinol-cytochrome c reductase core protein I (UQCRC1), a key component of mitochondrial complex III, is generally upregulated in PC and produces extracellular ATP (eATP) to promote PC progression. Here, we sought to investigate whether the oncogenic property of UQCRC1 is generated through its effects on natural killer (NK) cells in the TME. We found that UQCRC1 overexpression in PC cells inhibited cytotoxicity of NK cells, as well as the infiltration of NK cells toward PC, whereas knockdown of UQCRC1 enhanced the cytotoxicity and chemotaxis of NK cells. Adoptive NK cell therapy in the subcutaneous mouse model and CIBERSORTx analysis with human PC specimens confirmed UQCRC1 elicited immunosuppressive effects on NK cells. Such UQCRC1-induced impairment of NK cells was mediated by eATP and its metabolite adenosine via P2Y11R and A2AR, respectively. Mechanistically, we found the UQCRC1/eATP axis reduced the expression of chemokine CCL5 in cancer cells and altered the balance of activating receptor DNAM-1 and inhibitory receptor CD96 on NK-92MI cells, resulting in decreased chemotaxis and exhausted phenotype of NK-92MI cells. Taken together, our study provides the evidence to support a novel mechanism by which energy metabolism change in cancer cells remodels the TME and impedes NK cell surveillance. It also suggests that targeting UQCRC1 may be a potential combined strategy for PC immunotherapy.

Emerging immuno-therapies for advanced pancreatic cancer: An overview of available literature.

e16231 Background: Pancreatic cancer is the 11th most common cancer and represents 3.2% of all new cancer cases. But it is the third leading cause of cancer-related deaths with a five-year relative survival of only 10.8%. More than 50% of patients diagnosed with metastatic disease at initial presentation have 5-year relative survival of only 3.0%. Here, we explore the recent literature for the emerging role of immunotherapies and their outcomes for advanced pancreatic cancer. Methods: The literature search was conducted on PubMed, Embase, Cochrane, and ClinicalTrials.gov from inception to January 2022 using MeSH terms' pancreatic neoplasms', 'immunotherapy,' and 'therapeutics'. The final analysis includes nine clinical trials that meet the inclusion criteria regarding immunotherapy for metastatic pancreatic cancer. Results: The combination of pembrolizumab and trametinib with stereotactic radiotherapy (SBRT) reported a median progression-free survival (PFS) and overall survival (OS) of 25 and 18 months compared to gemcitabine and SBRT combination of 22 and 16 months, respectively. Another study reported a median OS of 18 months with nivolumab along with operative irreversible electroporation to increase the bioavailability of nivolumab in the cancer cells. The EGFR targeted CAR T cells therapy was evaluated in 14 patients with advanced pancreatic cancer with a median OS of five months and an overall response rate (ORR) of 29%. Sotigalimab, an agonistic CD40 antibody combined with nivolumab, was found to have an ORR of 58%, PFS of 12 months, and OS of 20 months after a follow-up of almost 18 months. On the contrary, Bruton's tyrosine kinase inhibitors such as Acalabrutinib and Ibrutinib were found to have no OS benefit (median OS 3.8 and 5.3 months, respectively). Conclusions: Due to the high mortality associated with advanced pancreatic cancer, there is increasing interest in Novel immunotherapies-based approaches, with some showing promising results.[Table: see text]

Immunotherapy in Pancreatic Cancer: Why Do We Keep Failing? A Focus on Tumor Immune Microenvironment, Predictive Biomarkers and Treatment Outcomes.

Simple SummaryIn pancreatic cancer, immunotherapy and targeted therapies have not brought about the therapeutic revolution that has been observed in other malignancies. Among the reasons to explain this difference is the possibly crucial role played by the pancreatic tumor microenvironment, which has unique features and is different from that of other neoplasms. The aim of this review is to provide a comprehensive overview of the distinctive tumor immune microenvironment of pancreatic cancer and to summarize existing data about the use of immunotherapy and immune biomarkers in this cancer.The advent of immunotherapy and targeted therapies has dramatically changed the outcomes of patients affected by many malignancies. Pancreatic cancer (PC) remains one the few tumors that is not treated with new generation therapies, as chemotherapy still represents the only effective therapeutic strategy in advanced-stage disease. Agents aiming to reactivate the host immune system against cancer cells, such as those targeting immune checkpoints, failed to demonstrate significant activity, despite the success of these treatments in other tumors. In many cases, the proportion of patients who derived benefits in early-phase trials was too small and unpredictable to justify larger studies. The population of PC patients with high microsatellite instability/mismatch repair deficiency is currently the only population that may benefit from immunotherapy; nevertheless, the prevalence of these alterations is too low to determine a real change in the treatment scenario of this tumor. The reasons for the unsuccess of immunotherapy may lie in the extremely peculiar tumor microenvironment, including distinctive immune composition and cross talk between different cells. These unique features may also explain why the biomarkers commonly used to predict immunotherapy efficacy in other tumors seem to be useless in PC. In the current paper, we provide a comprehensive and up-to-date review of immunotherapy in PC, from the analysis of the tumor immune microenvironment to immune biomarkers and treatment outcomes, with the aim to highlight that simply transferring the knowledge acquired on immunotherapy in other tumors might not be a successful strategy in patients affected by PC.

Combined anti-PD1 immunotherapy for patient with advanced pancreatic cancer: A case report

Pancreatic cancer (PC) is a highly lethal malignancy with a dismal 5-year survival rate. The current treatment modalities for the treatment-associated toxicity of immunotherapy-based approaches are limited. Immunotherapy for PC was needed to be further investigated. This report illustrates the combined use of anti PD-1 immunotherapy with other therapeutic strategies for cancer pain. In this case, a patient with PC was treated with surgical resection, chemotherapy, molecular targeted medicine, and anti-PD1 immunotherapy. The survival period of the patient was more than 6 years since diagnosis. Finally, we will present our perspective on the future development of immunotherapy for PC. In a word, this case report sheds lights on information that would be helpful for more rigorous exploration of PC treatments.

Role of TFRC as a Novel Prognostic Biomarker and in Immunotherapy for Pancreatic Carcinoma.

Objective: To explore the expression of the transferrin receptor (TFRC) gene in pancreatic cancer and to analyze the pathogenesis and immunotherapy of TFRC in patients using bioinformatics methods. Methods: We used public data from the cancer genome atlas (TCGA) and gene expression omnibus databases to explore the expression level of the TFRC gene in pancreatic cancer patients. At the same time, we analyzed the correlation between the TFRC gene expression and patient survival, and further analyzed the correlation between TFRC and survival time of patients with different clinicopathological characteristics. Co-expressed genes and pathway enrichment analyses were used to analyze the mechanism of the TFRC in the occurrence and development of pancreatic cancer. Ultimately, we used the R software to examine the relationship between TFRC and immune phenotypes and immune cell infiltration using the TCGA database. Results: The results of the study showed that TFRC is highly expressed in pancreatic cancer tissue. The upregulated expression of TFRC was negatively correlated with the survival in patients with pancreatic cancer. The bioinformatics analysis showed that TFRC plays a role in the occurrence and development of pancreatic cancer mainly through signaling pathways (including cell adhesion molecule binding, condensed chromosomes, chromosome segregation, and cell cycle checkpoints). Finally, TFRC is associated with immune phenotypes and immune cell infiltration, which may influence immunotherapy. Conclusion: TFRC is significantly increased in pancreatic cancer and is associated with a poor prognosis. Moreover, research on TFRC may generate new ideas for the immunotherapy of pancreatic cancer.

Immunotherapy in pancreatic cancer—an emerging role: a narrative review

Immunotherapy is the fastest growing branch in oncology that have already revolutionized the treatment of few solid cancers. The number of immunotherapy trials for pancreatic cancer (PC) is growing but the vast number of different agents used make it difficult to comprehend a possible success trait of a certain type of immunotherapy. The aim of this review is to summarize and critically evaluate the outcome of immunotherapy trials for PC intended to aid the comprehensiveness for the treating physicians. A PubMed search was performed to identify clinical trials in patients with PC, published in English from year 2000 to June 2021 and using combination of the terms immunotherapy, PC, and cross-checked the bibliography of the revised literature as the dublettes have been removed. Studies were divided into three groups depending on what immune components have been applied: passive products (peptides, antibodies, etc.), antigen-presenting cells, and adoptive cell transfer trials. The vast majority of trials, including those from most recent years, used passive products of the immune system-peptide vaccines and antibodies. The administration was often parallel to chemotherapy that was prevalently gemcitabine-based. Although immunological responses have been detected, the clinical efficacy was very limited. Trials with check point inhibitors did not show survival advantage. Dendritic cell (DC) vaccines have been associated with some clinical objective response and prolonged survival in few patients with delayed type hypersensitivity reactions. Trials with adoptive transfer therapy are lacking. The very few trials with lymphokine-activated killer (LAK)/cytokine-induced killer (CIK) cells tested only in Asian population have resulted in some clinical effects with prolonged survival. In none of the trials have the patients been preconditioned before receiving immunotherapy. Although the clinical effectiveness in the majority of the reported trials has been limited, the immunological effects observed in almost all trials show a proof of concept-that immunotherapy can work. Careful re-evaluation of the clinical premises and focus on combination and cell therapy may be the way to achieve improved survival by immunotherapy in PC.

Identification of a DNA repair 9-gene signature for the overall survival prediction of pancreatic cancer

BackgroundPancreatic cancer (PC) is one of the deadliest malignant tumors with poor prognosis. DNA repair genes can be promising candidate biomarkers in PC. The aim of this study was to generate and clinically validate a novel gene signature to effectively predict the prognosis of patients with PC. MethodsThe PC-related data of cancer genome atlas database and the GSE62452, GSE85916 of the gene expression omnibus database were downloaded for signature and further validation. According to the risk score, Patients were classified into high and low risk score groups. We analyzed drug sensitivity base on genomics of drug sensitivity in cancer and immune cell infiltration via CIBERSORT between the two groups. Gene set variation Analysis was performed to analyze signaling pathways affecting prognosis. ResultsNine genes (F5, CD36, TRIM29, VCAM1, ANO1, ERBB3, MMP28, NEK2 and MET) were identified to construct a prognostic model. Patients with lower risk score had significantly favorable overall survival in the TCGA database, GSE62452 and GSE85916 dataset (p < 0.05). GSVA analysis showed differences in 13 important signaling pathways between high and low risk score groups. Immune-modulating factors (ADORA2A, CD160, KDR, BTLA) were highly expressed in the low-risk group. The risk score significantly affected the sensitivity of patients to Gefitinib and Dasatinib (p < 0.005) and associated with overall survival and grade (p < 0.05). ConclusionThis study evaluated a potential prognostic signature base on nine DNA repair genes and provides a way to explore the mechanism of DNA repair genes and immunotherapy in pancreatic cancer.

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.

Advance of T regulatory cells in tumor microenvironment remodeling and immunotherapy in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive, deadly, and is rarely diagnosed early. Regulatory T cells (Treg) are a multifunctional class of immunosuppressive T cells that help maintain immunologic homeostasis and participate in autoimmune diseases, transplants, and tumors. This cell type mediates immune homeostasis, tolerance, and surveillance and is associated with poor outcomes in PDAC. Tregs remodel the tumor immune microenvironment, mediate tumor immune escape, and promote tumor invasion and metastasis. A promising area of research involves regulating Tregs to reduce their infiltration into tumor tissues. However, the complexity of the immune microenvironment has limited the efficacy of immunotherapy in PDAC. Treg modulation combined with other treatments is emerging. This review summarizes the mechanisms of Tregs activity in tumor immune microenvironments in PDAC and the latest developments in immunotherapy and clinical trials.

Turning towards nonimmunoreactive tumors: Evaluation of cancer-associated fibroblasts enables prediction of the immune microenvironment and treatment sensitivity in pancreatic cancer

Increasing evidence has confirmed that cancer-associated fibroblasts (CAFs) recruit and induce regulatory T cells (Tregs) and macrophages but inhibit cytotoxic T lymphocyte infiltration to a certain extent, indicating that CAFs have a significant influence on the immunosuppressive microenvironment. However, the effect of CAFs on the immune microenvironment and immunotherapy response in pancreatic cancer remains unclear. Our research identified remarkable variation in CAF-associated molecules in multiple cancer types at the genetic and transcriptome levels. Two phenotypes were identified for 476 pancreatic cancer samples, and the different phenotypes exhibited significant variation in immune and inflammatory characteristics. Phenotype 1 exhibited higher levels of immune infiltration and lower expression of tumor-associated gene signatures than phenotype 2. We used a multipart approach to assess the prognostic value of CAF-associated molecules and constructed a CAF score model that could accurately predict patient prognosis. The CAF score accurately predicted infiltrating immune cell abundance, chemosensitivity, and the response to immunotherapy. Additionally, we found that the CAF-associated molecule FGFR4 may promote the proliferation and migration and inhibit the apoptosis of pancreatic cancer cells and is correlated with immune infiltration, suggesting its potential role as an oncogene. CAFs may promote the malignant biological behavior of pancreatic cancer through FGFR4. In summary, our research highlights potential relationships of the dysregulation of CAF-associated molecules with genome alterations and carcinogenesis in multiple malignancies. Our CAF-associated phenotypes and scoring system may enhance the understanding of pancreatic cancer chemotherapy sensitivity and immunotherapy response, providing new insights for personalized chemotherapy and immunotherapy.

Stroma Regulation Combined with IL12 Enhances Immunotherapy Effect in Pancreatic Cancer

Introduction: In order to enhance the efficacy of immunotherapy of pancreatic cancer, we combined the pancreatic cancer stroma regulating drug JQ1 with IL12 to explore the therapeutic effect of this strategy on pancreatic cancer.

TNFSF9 promotes metastasis of pancreatic cancer by regulating M2 polarization of macrophages through Src/FAK/p-Akt/IL-1β signaling

The effect of tumor necrosis factor superfamily member 9 (TNFSF9) on the metastasis of pancreatic cancer (PC) and the underlying mechanism remain unclear. We studied the expression of TNFSF9 in pancreatic cancer and its relationship with immune cells. We further explored the effect of TNFSF9 on pancreatic cancer metastasis by inducing macrophage polarization, and evaluated the expression of Src/FAK/p-Akt/IL-1β signals in macrophages after knocking down TNFSF9. The data shows that TNFSF9 expression is elevated in pancreatic cancer and is related to the poor prognosis of patients with pancreatic cancer. In addition, TNFSF9 may induce the M2 polarization of macrophages through Src/FAK/p-Akt/IL-1β signals, thereby promoting the migration of pancreatic cancer cells. In conclusion, our data reveals that TNFSF9 may become a predictive biomarker of pancreatic cancer and provides a new intervention target for the immunotherapy of pancreatic cancer.

The Immunotherapy for Colorectal Cancer, Lung Cancer and Pancreatic Cancer.

Immunotherapy is a novel anti-cancer method which employs a different mechanism to conventional treatment. It has become a significant strategy because it provides a better or an alternative option for cancer patients. Recently, immunotherapy has been increasingly approved for the treatment of cancer; however, it has various limitations; for instance, it is only suitable for specific patients, the response rate is still low in most cases, etc. Colorectal cancer, lung cancer and pancreatic cancer are known as three major death-causing cancers in most countries. In this review, we discuss immunotherapeutic treatment for these three cancers, and consider the option, prospects and limitations of immunotherapy. The development of immunotherapy should focus on the discovery of biomarkers to screen suitable patients, new targets on tumors, neoadjuvant immunotherapy and the combination of immunotherapy with conventional therapeutic methods. We can expect that immunotherapy potentially will develop as one of the best therapies for patients with advanced cancer or poor responses to traditional methods.

Hydroxytyrosol Inhibits MDSCs and Promotes M1 Macrophages in Mice With Orthotopic Pancreatic Tumor.

The poor immunotherapy of pancreatic cancer is mainly due to its complex immunosuppressive microenvironment. The Mediterranean diet contributes to low cancer incidence. Hydroxytyrosol (HT) derived from olive oil has multiple health-promoting effects, but its therapeutic effect on pancreatic cancer remains controversial. Here, we evaluated the inhibitory effect of HT on mouse pancreatic cancer, and the effect of HT on the immune microenvironment. We found that HT can inhibit the proliferation of Panc 02 cells through signal transducer and activator of transcription (STAT) 3/Cyclin D1 signaling pathway. In the tumor-bearing mice treated with HT, the orthotopic pancreatic tumors were suppressed, accompanied by a decrease in the proportion of myeloid-derived suppressor cells (MDSCs) and an increase in the proportion of M1 macrophages. In addition, we found that HT inhibited the expression of immunosuppressive molecules in bone marrow (BM)-derived MDSCs, as well as down-regulated CCAAT/enhancer-binding protein beta (C/EBPβ) and phosphorylation of STAT3. Moreover, HT enhanced the anti-tumor effect of anti-CD47 antibody in vivo. HT combined with plumbagin (PLB) induced more Panc 02 cells death than HT or PLB alone. This combination therapy not only inhibited the accumulation of MDSCs, but also promoted the infiltration of CD4+ and CD8+ T cells in the tumors. In summary, HT is a potential immunomodulatory drug for the treatment of pancreatic cancer.

The Function of cGAS-STING Pathway in Treatment of Pancreatic Cancer.

The activation of stimulator of interferon genes (STING) signalling pathway has been suggested to promote the immune responses against malignancy. STING is activated in response to the detection of cytosolic DNA and can induce type I interferons and link innate immunity with the adaptive immune system. Due to accretive evidence demonstrating that the STING pathway regulates the immune cells of the tumor microenvironment (TME), STING as a cancer biotherapy has attracted considerable attention. Pancreatic cancer, with a highly immunosuppressive TME, remains fatal cancer. STING has been applied to the treatment of pancreatic cancer through distinct strategies. This review reveals the role of STING signalling on pancreatic tumors and other diseases related to the pancreas. We then discuss new advances of STING in either monotherapy or combination methods for pancreatic cancer immunotherapy.

Comprehensive Analysis of m6A RNA Methylation Regulators and the Immune Microenvironment to Aid Immunotherapy in Pancreatic Cancer.

Pancreatic cancer (PAAD) is one of the most malignant cancers and immune microenvironment has been proved to be involved in pathogenesis of PAAD. m6A modification, related to the expression of m6A regulators, participates in the development of multiple cancers. However, the correlation between m6A regulators and immune microenvironment was largely unknown in PAAD. And because of the small sample size of pancreatic cancer in the TCGA database, it is not enough to draw a convincing conclusion. In the present study, we downloaded seven pancreatic cancer datasets with survival data and removed batch effects among these datasets to be used as the PAAD cohort to analyze the immune landscape of PAAD and the expression pattern of m6A regulators and divided the integrated dataset into cluster 1 and cluster 2 by consensus clustering for m6A regulators. Lower m6A regulators were found to be related to higher immune cell infiltration and a better survival. Moreover, we identified six m6A regulators and constructed the prognostic signature of m6A regulators. Patients with low-risk score had a higher response to immune checkpoint inhibitor and a longer overall survival. To figure out the underlying mechanism, we analyzed the cancer immunity cycle, most altered genes, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) in risk subtypes. In summary, the present study proved m6A regulators modulated the PAAD immune microenvironment. And risk scores served as predictive indicator for immunotherapy and played a prognostic role for PAAD patients. Our study provided novel therapeutic targets to improve immunotherapy efficacy.

Uncovering key targets of success for immunotherapy in pancreatic cancer

ABSTRACT Introduction Despite available treatment options, pancreatic ductal adenocarcinoma (PDAC) is frequently lethal. Recent immunotherapy strategies have failed to yield any notable impact. Therefore, research is focussed on unearthing new drug targets and therapeutic strategies to tackle this malignancy and attain more positive outcomes for patients. Areas covered In this perspective article, we evaluate the main resistance mechanisms to immune checkpoint inhibitors (ICIs) and the approaches to circumvent them. We also offer an assessment of concluded and ongoing trials of PDAC immunotherapy. Literature research was performed on Pubmed accessible through keywords such as: ‘pancreatic ductal adenocarcinoma,’ ‘immunotherapy,’ ‘immunotherapy resistance,’ ‘immune escape,’ ‘biomarkers.’ Papers published between 2000 and 2021 were selected. Expert opinion The tumor microenvironment is a critical variable of treatment resistance because of its role as a physical barrier and inhibitory immune signaling. Promising therapeutic strategies appear to be a combination of immunotherapeutics with other targeted treatments. Going forward, predictive biomarkers are required to improve patient selection. Biomarker-driven trials could enhance approaches for assessing the role of immunotherapy in PDAC.

Understanding the immune response and the current landscape of immunotherapy in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor with high lethality. Even with surgery, radiotherapy, chemotherapy, and other locoregional or systemic therapies, the survival rates for PDAC are low and have not significantly changed in the past decades. The special characteristics of the PDAC’s microenvironment and its complex immune escape mechanism need to be considered when designing novel therapeutic approaches in this disease. PDAC is characterized by chronic inflammation with a high rate of tumor-associated macrophages and myeloid-derived suppressor cells and a low rate of natural killer and effector T cells. The pancreatic microenvironment is a fibrotic, microvascularized stroma that isolates the tumor from systemic vascularization. Immunotherapy, a novel approach that has demonstrated effectiveness in certain solid tumors, has failed to show any practice-changing results in pancreatic cancer, with the exception of PDACs with mismatch repair deficiency and high tumor mutational burden, which show prolonged survival rates with immunotherapy. Currently, numerous clinical trials are attempting to assess the efficacy of immunotherapeutic strategies in PDAC, including immune checkpoint inhibitors, cancer vaccines, and adoptive cell transfer, alone or in combination with other immunotherapeutic agents, chemoradiotherapy, and other targeted therapies. A deep understanding of the immune response will help in the development of new therapeutic strategies leading to improved clinical outcomes for patients with PDAC.

Current status of immunotherapy for pancreatic cancer

Current status of immunotherapy for pancreatic cancer

S94 Exceptional Responders to Immunotherapy in Pancreatic Cancer: A Multi-Institutional Case Series

S94 Exceptional Responders to Immunotherapy in Pancreatic Cancer: A Multi-Institutional Case Series