T-cell programming in pancreatic adenocarcinoma: a review

Despite recent advancements in multimodal therapy, pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. In the era of burgeoning immune therapies against previously difficult-to-treat malignancies, there has been growing interest in activating the immune system against PDA; however, unlike in other cancers such as melanoma and lymphoma, immunotherapy has not yielded many clinically significant results. To harness these mechanisms for therapeutic use, an in-depth understanding of T-cell programming in the immune microenvironment of PDA must be achieved. The outcome of T-cell programming against pathogens or cancer depends on the uptake and presentation of foreign antigens by dendritic cells and macrophages to T cells, and the expression of various co-stimulatory molecules and cytokines. Subsequent immune responses are kept in check via regulatory mechanisms such as immune checkpoints (for example, programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4)), as well as other immunosuppressive cell types such as regulatory T cells (T_reg) and M2 macrophages. PDA presents a challenge from the perspective of immune therapy because of many immunosuppressive mechanisms at play in its microenvironment. The tumor itself produces IL-10 and transforming growth factor beta (TGF-β) that downregulate T-cell activation as well as the activity of antigen-presenting cells. At the same time, PDA also appears to recruit more regulatory elements into its milieu; higher infiltration of T_reg, for instance, has been associated with poorer prognosis in PDA patients. M2 macrophages and myeloid-derived suppressive cells are also highly prevalent in the tumor microenvironment. T cells in PDA have high expression of PD-1, whereas the tumor has high expression of PD-L1, which likely inhibits activation of tumor antigen-specific T cells. Many of these immunosuppressive mechanisms have been targeted as potential immune therapies of PDA. Immune checkpoint inhibitors, which target PD-1 and CTLA-4, have been shown to be effective in other cancers such as melanoma; however, they have not demonstrated outcome benefits in PDA so far. Other novel investigational approaches under study currently include inhibiting the homing of immunosuppressive cell types to the tumor milieu, as well as vaccines designed to boost the adaptive response to PDA antigens. As our understanding of the nuanced and complex interactions of the immune microenvironment expands, more targeted approaches can be taken toward achieving therapeutic success in immune therapy against PDA.