Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma.

The most frequent mutated oncogene family in the history of human cancer is the RAS gene family, including NRAS, HRAS, and, most importantly, KRAS. A hallmark of pancreatic cancer, recalcitrant cancer with a very low survival rate, is the prevalence of oncogenic mutations in the KRAS gene. Due to this fact, studying the function of KRAS and the impact of its mutations on the tumor microenvironment (TME) is a priority for understanding pancreatic cancer progression and designing novel therapeutic strategies for the treatment of the dismal disease. Despite some recent enlightening studies, there is still a wide gap in our knowledge regarding the impact of KRAS mutations on different components of the pancreatic TME. In this review, we will present an updated summary of mutant KRAS role in the initiation, progression, and modulation of the TME of pancreatic ductal adenocarcinoma (PDAC). This review will highlight the intriguing link between diabetes mellitus and PDAC, as well as vitamin D as an adjuvant effective therapy via TME modulation of PDAC. We will also discuss different ongoing clinical trials that use KRAS oncogene signaling network as therapeutic targets.

Neutrophil-lymphocyte ratio (NLR) was associated with prognosis and immunomodulatory in patients with pancreatic ductal adenocarcinoma (PDAC).

Although the oncological outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) have markedly improved over the past decade, the survival prediction is still challenging. The aim of this study was to investigate the prognostic value of neutrophil-lymphocyte ratio (NLR) and analyze the relationship of between the NLR and immune cells phenotypes in patients with PDAC. Sixty-seven consecutive patients with PDAC were recruited in this study. Life-table estimates of survival time were calculated according to the Kaplan and Meier methodology. The phenotypic T cells subclasses were evaluated by flow cytometry. All the 67 patients in this study were treated with surgical resection and among them, 46 patients received adjuvant chemotherapy. Receiver operating characteristic (ROC) curves analysis was performed to compare prognostic value of NLR with CA199. We found that the Harrell's area under ROC (AUROC) for the NLR to predict overall survival (OS) (0.840; 95% CI, 0.766-0.898) was significantly higher than that of the CA199 levels. After that we stratified all patients into NLR > 2.5 (n = 42) and NLR ≤ 2.5 (n = 25) groups according to the OS of patients with PDAC. Survival analysis showed that patients with NLR ≤ 2.5 had significantly favorable OS and progressive free survival (PFS) compared with patients with NLR > 2.5. The CD3+ and CD8+/CD28+ T cell subsets were significantly increased in patients with NLR ≤ 2.5 (P<0.05), while the CD8+/CD28- and CD4+/CD25+ cell subsets were significantly decreased in patients with NLR ≤ 2.5 (P<0.05). In conclusion, a high NLR value independently predicts poor survival in patients with PDAC after surgical resection. The NLR was closely related with immune cells phenotypes The NLR may help oncologists evaluate outcomes of patients received surgical resection and chemotherapy to choose alternative therapies for patients with high NLR value.

Local and systemic immunosuppression in pancreatic cancer: Targeting the stalwarts in tumor's arsenal.

Late detection, compromised immune system, and chemotherapy resistance underlie the poor patient prognosis for pancreatic ductal adenocarcinoma (PDAC) patients, making it the 3rd leading cause of cancer-related deaths in the United States. Cooperation between the tumor cells and the immune system leads to the immune escape and eventual establishment of the tumor. For more than 20 years, sincere efforts have been made to intercept the tumor-immune crosstalk and identify the probable therapeutic targets for breaking self-tolerance toward tumor antigens. However, the success of these studies depends on detailed examination and understanding of tumor-immune cell interactions, not only in the primary tumor but also at distant systemic niches. Innate and adaptive arms of the immune system sculpt tumor immunogenicity, where they not only aid in providing an amenable environment for their survival but also act as a driver for tumor relapse at primary or distant organ sites. This review article highlights the key events associated with tumor-immune communication and associated immunosuppression at both local and systemic microenvironments in PDAC. Furthermore, we discuss the approaches and benefits of targeting both local and systemic immunosuppression for PDAC patients. The present articles integrate data from clinical and genetic mouse model studies to provide a widespread consensus on the role of local and systemic immunosuppression in undermining the anti-tumor immune responses against PDAC.

Utilizing Salmonella to treat solid malignancies.

Despite intensive research into novel treatment strategies for cancer, it remains the second most common cause of death in industrialized populations. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with dismal prognosis. Currently, surgical resection offers the best chance for extended survival, yet recurrence remains high and is associated with poor outcome. Systemic treatment has evolved from non-specific, cytotoxic chemotherapy to the use of cancer-targeting agents, profoundly changing treatment approaches in the metastatic and adjuvant settings. One promising approach, highlighted in this review, uses the inherent capacity of Salmonella to colonize and eliminate solid tumors.

Low total lymphocyte count is associated with poor survival in patients with resected pancreatic adenocarcinoma receiving a GM-CSF secreting pancreatic tumor vaccine.

BACKGROUND: Low total lymphocyte count (TLC) and lymphocyte-to-neutrophil ratio have been found to be poor prognostic indicators in several different tumor types at various stages. Although immune-based therapies are under rapid development, it is not known whether baseline complete blood counts, particularly lymphocytes, are associated with the clinical outcomes of patients receiving immunotherapies. METHODS: We performed a retrospective analysis of complete blood count for 59 patients enrolled onto a phase II trial evaluating the integration of an adjuvant immunotherapy-irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting allogeneic pancreatic tumor vaccine (GVAX)-with standard chemoradiation. RESULTS: After adjusting for nodal status, individuals with a TLC of <1,500 cells/mm(3) (10 patients) had significantly higher risk, both in terms of overall survival (OS) [adjusted hazard ratio 2.63, 95 % confidence interval (CI) 1.22-5.67, p = 0.013] and progression-free survival (adjusted hazard ratio 3.07, 95 % CI 1.03-6.93, p = 0.003), compared to those with a TLC of ≤ 1,500 cells/mm(3) (49 patients). Adjuvant chemoradiation significantly reduced lymphocyte counts from baseline values. Patients with suppression of their lymphocytes to <500 cells/mm(3) after chemoradiation also had shorter disease-free and OS. CONCLUSIONS: Immunosuppressive conditions associated with surgical procedures and chemoradiation may affect the efficacy of immunotherapy.

Human pancreatic carcinoma cells secrete bioactive interleukin-18 after treatment with 5-fluorouracil: implications for anti-tumor immune response.

Recently we observed that pancreatic carcinoma cell lines constitutively express Interleukin-18 (IL-18). Bioactive IL-18 induces Interferon (IFN)-gamma production, Fas Ligand (FasL) expression, and inhibits angiogenesis, raising the issue of anti-tumor effects of a tumor-derived cytokine and motivating a more detailed analysis of IL-18 production in pancreatic carcinoma cells. This analysis included the study of effects of chemotherapeutic drugs (5-fluorouracil [5-FU], gemcitabine, cisplatin) commonly used in the treatment of pancreatic cancer patients on IL-18 production and processing. IL-18 expression and post-translational processing were determined using RT-PCR, immunoblot and ELISA in pancreatic carcinoma cell lines and in tumor tissue and serum samples from pancreatic carcinoma patients in the presence and absence of chemotherapeutic drugs. We describe expression of IL-18 in pancreatic carcinoma cells and tissues associated with significantly elevated IL-18 levels in patients sera. Specifically, Capan-2 pancreatic tumor cells produced and secreted precursor IL-18 with no apparent biological activity. However, the chemotherapeutic agent 5-FU, by inducing Caspase-1 and Caspase-3 activation, induced secretion of proteolytically processed mature and degraded IL-18 species, respectively, in Capan-2 cells. Conditioned medium from 5-FU-treated but not control Capan-2 cells induced IFN-gamma production by activated T cells in an IL-18-dependent manner. Furthermore, adjuvant polychemotherapy including 5-FU significantly increased serum levels of mature, bioactive IL-18 in pancreatic carcinoma patients. Treatment of pancreatic cancer cells with 5-FU induced Caspase-dependent processing of pro-IL18 leading to the secretion of biologically active IL-18. These findings delineate a novel mechanism by which chemotherapeutic agents may modulate local anti-tumor cell-mediated immune responses.