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.

Pancreatic ductal adenocarcinoma (PDAC) interacts closely with the tumor microenvironment (TME). The TME is remodeled by crosstalk between pancreatic cancer cells and stromal cells, and is critical for cancer progression. Extracellular vesicles (EVs), including exosomes and microvesicles, help facilitate an exchange of information both within the TME and to distant organs. EVs have also been identified as potential diagnostic biomarkers, therapeutic targets, and drug carriers for pancreatic cancer treatment. Thus, understanding the selective packaging of EVs cargo and its mechanistic impact will increase our understanding of cancer biology. In this review, we collect and analyze recent findings of the pancreatic cancer-stromal cell interactions mediated by EVs and the mechanisms involved in cancer-related immunity and chemoresistance. These studies demonstrate the vital role of EVs in pancreatic cancer reprogramming and TME remodeling. We also summarize the EVs identified as potential PDAC diagnostic biomarkers and possible therapeutic targets. This greater understanding is a promising avenue for transitioning EVs from bench to bedside.Graphical Abstract

Inflammation involves interactions between various immune cells, inflammatory cells, chemokines and cytokines in pancreatic cancer. Cancer cells as well as surrounding stromal and inflammatory cells establish an inflammatory tumor microenvironment (TME). Inflammation is closely associated with immunity. Meanwhile, immune cells are involved in both inflammation and immune response. Tumor-promoting inflammation and tumor-suppressive immunity are two main characteristics of the tumor microenvironment in pancreatic cancer. Yet, the mechanism of inflammation and immune response in pancreatic cancer development is still unclear due to the dual role of some cytokines and the complicated crosstalk between tumor and stromal components in TME. In this review, we outline the principal cytokines and stromal cells in the pancreatic TME that are involved in the tumor-promoting and immunosuppressive effects of inflammation, and discuss the interaction between inflammation and stromal components in pancreatic cancer progression. Moreover, the clinical approaches based on targeting TME in pancreatic cancer are also summarized. Defining the mechanisms of interplay between inflammation and stromal components will be essential for further development of anti-cancer therapies.

Background: Systemic nutritional and inflammatory markers, which are easy to measure are associated with the progression and prognosis of many cancers. Nevertheless, among the various available indicators, optimal prognostic indicators for patients with early-onset colorectal cancer have not been identified. Therefore, the aim of this study was to identify optimal nutritional and inflammatory markers for early-onset colorectal cancer and examine the relationship between systemic nutritional and inflammatory markers before treatment and survival in patients with early-onset colorectal cancer.Methods: We retrospectively collected data from 236 eligible patients with early-onset colorectal cancer. Area under the prognostic curve (AUC) and concordance index (C-index) were used to compare seven systemic nutritional and inflammatory markers to identify the optimal inflammatory immune markers. Univariate and multivariate COX regression analyses were used to evaluate the prognostic value of indicators in the total study population and different subgroups.Results: The AUC and C-index showed that the systemic immune inflammation index (SII) and geriatric nutrition risk index (GNRI) had higher prognostic values than other systemic nutritional and inflammatory indicators. Compared with patients in the low SII group, those in the high SII group had lower overall survival (HR, 4.42, 95% CI, 2.36–8.27, p = 0.000). Compared with patients in the high GNRI group, those in the low GNRI group had lower overall survival (HR, 0.33, 95% CI, 0.19–0.56, p = 0.000). SII was negatively associated with GNRI (R = −0.3, p < 0.001), and both were correlated with the tumor stage.Conclusion: SII and GNRI are suitable nutritional and inflammatory factors for predicting OS in patients with early-onset colorectal cancer; high SII and low GNRI were correlated with worse prognoses. Identifying the high inflammatory state and low nutritional state of patients before surgery and conducting active and timely therapeutic interventions could improve patient prognosis.

Long noncoding RNAs (lncRNAs) are a new class of regulators. LncRNAs are defined as endogenous transcribed RNA molecules with transcript length of >200 nt. Accumulating evidence has shown that lncRNAs are involved in many physiological processes such as cell cycle regulation, cell apoptosis and survival, cancer migration and metabolism. However, the biological and molecular mechanisms of lncRNAs in pancreatic cancer are still unclear. Recent studies have reported that many lncRNAs are dysregulated in pancreatic cancer and closely associated with tumorigenesis, diagnosis and prognosis. In this review, we described the regulation and functional role of lncRNAs and the potential underlying mechanism involved in pancreatic cancer, outlined the roles of lncRNA in pancreatic cancer, and discussed the potential possibility of lncRNAs as therapeutic targets in clinical practice. Moreover, the potential of lncRNAs used as sensitive biomarkers for diagnosis, prognosis and prediction of response to therapy in pancreatic cancer will also be discussed.