Current immunotherapeutic approaches in pancreatic cancer

Abstract

Pancreatic cancer is a highly aggressive and notoriously difficult to treat. As the vast majority of patients are diagnosed at advanced stage of the disease, only a small population is curative by surgical resection. Although gemcitabine-based chemotherapy is typically offered as standard of care, most patients do not survive longer than 6 months. Thus, new therapeutic approaches are needed. Pancreatic cancer cells that develop gemcitabine resistance would still be suitable targets for immunotherapy. Therefore, one promising treatment approach may be immunotherapy that is designed to target pancreatic-cancer-associated antigens. In this paper, we detail recent work in immunotherapy and the advances in concept of combination therapy of immunotherapy and chemotherapy. We offer our perspective on how to increase the clinical efficacy of immunotherapies for pancreatic cancer.

Figure 1

CTL induction by DCs. Antigens are taken up and degraded into peptide fragments by antigen-presenting cells, such as immature DCs. DCs process tumor-derived peptides and MHC class I peptides derived from DCs. They form MHC class I-peptide complexes, in the endoplasmic reticulum, which are transported to the surface of DCs and presented to CD8+ T cells. DCs also synthesize MHC class II peptides in the endoplasmic reticulum, which are transported to the cytoplasm where MHC class II-peptide complexes are assembled with tumor-derived peptides and presented to CD4+ T cells. The CD4+ T cells produce increased amounts of IL-2, which drives CD8+ T-cell proliferation. CD8+ T cells then become CTL, which can destroy cancer cells through effector molecules such as granzyme B and perforin.

Figure 2

Immune homeostasis. Upon TCR-mediated cell activation, naive CD4 T cells can differentiate into four major lineages, Th1, Th2, Th17, and Treg cells that participate in different types of immune responses. The Th1 cells produce IFN-γ and IL-2, resulting in induction of CD8+ CTLs. Th2 cells secrete IL-4 and IL-10. The Th2 response is associated with the humoral, antibody-based antitumor response. Th17 cells secrete IL-17 and IL-22, eliciting tissue inflammation implicated in autoimmunity. Treg cells that secrete TGF-β and IL-10 suppress effector Th1 or Th2 cells.

Figure 3

Pancreatic cancers induce an immunosuppressive tumor microenvironment. Pancreatic cancer cells secrete various immunosuppressive factors such as VEGF, IL-6, IL-10, TGF-β, Fas-L, IDO, PD-L1, and microvesicles, all of which promote the accumulation of TAM, MDSC, or tolerogenic DC. These immunosuppressive cells inhibit antitumor immunity by various mechanisms, including depletion of arginine and elaboration of ROS and NO. An immunosuppressive tumor microenvironment induced by pancreatic cancers suppresses CD8+ CTL function through secretion of IL-10 and TGF-β from Treg cells. All contribute to pancreatic cancer-induced immune suppression.

Figure 4

Strategies to deliver defined or whole antigens to DCs. DCs used for cancer vaccines have been generated from the peripheral blood monocytes of the patients using cytokines including GM-CSF and IL-4. To generate antigen-specific CTL response against tumor cells, DCs have been loaded with defined or whole tumor-associated antigens. For example, DCs loaded with synthetic peptide, antigenic DNA, or RNA have been used. Moreover, whole tumor-associated antigens including defined and unidentified have been also loaded to DCs.

Figure 5

Combination therapies of immunotherapy and standard radio- and chemotherapy. Currently applied standard therapies such as radio- and chemotherapy target bulk cancer cells that are less resistant than cancer stem cells. This leads to initial regression of the tumor mass but eventually regrowth from residual CSCs. Combined therapies of standard therapies and immunotherapeutic approach targeting CSCs would cut off the rejuvenating supply of CSCs and resulted in tumor eradication.