Immunotherapy in pancreatic adenocarcinoma-overcoming barriers to response

Abstract

Pancreatic adenocarcinoma (PAC) remains one of the leading causes of cancer-related death. Despite multiple advances in targeted and immune therapies, the 5-year survival in advanced PAC remains poor. In this review, we discuss some of the unique aspects of the tumor microenvironment (TME) in PAC that may contribute to its resistance to immune therapies, as well as opportunities to potentially overcome some of these inherent barriers. Furthermore, we discuss strategies to enable immune therapies in PAC such as cytotoxic chemotherapy and radiation therapy, cancer vaccines, cytokine based therapy, oncolytic viruses, and adoptive T-cell therapy. Finally, we address a variety of targeted therapies as a strategy to further amplify immune responses in PAC.

Keywords: Pancreatic cancer; immunotherapy; targeted therapies; tumor microenvironment (TME).

Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

Figures

Figure 1

Immunomodulation of PAC: TC (tumor cell), PD-(L)1 [programmed death (ligand) 1], d (DAMP, damage associated membrane protein), BTK (bruton’s tyrosine kinase), JAK (janus associated kinase), DC (dendritic cell), PD-(L)1 (programmed death ligand 1). Cytotoxic chemotherapy and radiotherapy kill malignant cells by immunogenic cell death which results in exposure of DAMPs, which are subsequently taken up by DCs which subsequently prime T-cells to trigger a tumor-specific immune response. Immune checkpoint blockade can inhibit the inhibitory PD-1/PD-L1 interaction between TCs and T-cells that enhance anti-tumor immunity. CD40 agonists mediate T-cell dependent and independent mechanisms of tumor regression through enhancing antigen presentation by DCs and other antigen presenting cells (APCs). JAK inhibitors may inhibit pancreatic stellate cell activation and may reduce fibrotic extracellular matrix to enhance TC and immune cell interface. BTK inhibitors suppresses B-cell and macrophage mediated suppression of T-cells. Inhibition of immunosuppressive cytokines such as CCR2, CXCR4, and TGF-β, may enhance anti-tumor immune response through reduction of immunosuppressive monocytes, and interactions between pancreatic stellate cells and cancer cells.