Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment

J Exp Clin Cancer Res. 2019 Apr 15;38(1):162. doi: 10.1186/s13046-019-1153-8.


Background: Pancreatic cancer is one of the most lethal type of cancers, with an overall five-year survival rate of less than 5%. It is usually diagnosed at an advanced stage with limited therapeutic options. To date, no effective treatment options have demonstrated long-term benefits in advanced pancreatic cancer patients. Compared with other cancers, pancreatic cancer exhibits remarkable resistance to conventional therapy and possesses a highly immunosuppressive tumor microenvironment (TME).

Main body: In this review, we summarized the evidence and unique properties of TME in pancreatic cancer that may contribute to its resistance towards immunotherapies as well as strategies to overcome those barriers. We reviewed the current strategies and future perspectives of combination therapies that (1) promote T cell priming through tumor associated antigen presentation; (2) inhibit tumor immunosuppressive environment; and (3) break-down the desmoplastic barrier which improves tumor infiltrating lymphocytes entry into the TME.

Conclusions: It is imperative for clinicians and scientists to understand tumor immunology, identify novel biomarkers, and optimize the position of immunotherapy in therapeutic sequence, in order to improve pancreatic cancer clinical trial outcomes. Our collaborative efforts in targeting pancreatic TME will be the mainstay of achieving better clinical prognosis among pancreatic cancer patients. Ultimately, pancreatic cancer will be a treatable medical condition instead of a death sentence for a patient.

Keywords: Immunotherapy; Pancreatic cancer; Tumor microenvironment.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use
  • Biomarkers, Tumor
  • Cancer-Associated Fibroblasts / drug effects
  • Cancer-Associated Fibroblasts / immunology
  • Cancer-Associated Fibroblasts / metabolism
  • Clinical Studies as Topic
  • Combined Modality Therapy
  • Humans
  • Immunocompromised Host*
  • Immunomodulation / drug effects*
  • Immunotherapy
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism
  • Molecular Targeted Therapy
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Treatment Outcome
  • Tumor Microenvironment / drug effects*
  • Tumor Microenvironment / immunology*


  • Antineoplastic Agents, Immunological
  • Biomarkers, Tumor