Immune therapies in pancreatic ductal adenocarcinoma: Where are we now?

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, mostly due to its resistance to treatment. Of these, checkpoint inhibitors (CPI) are inefficient when used as monotherapy, except in the case of a rare subset of tumors harboring microsatellite instability (< 2%). This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC. The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancer-associated-fibroblast activation and transforming growth factor β secretion. Several strategies have recently been developed to overcome this immunosuppressive microenvironment. Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells. Ongoing studies are therefore exploring the association of CPI with vaccines, oncolytic viruses, MEK inhibitors, cytokine inhibitors, and hypoxia- and stroma-targeting agents. Adoptive T-cell transfer is also under investigation. Moreover, translational studies on tumor tissue and blood, prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.

Keywords: Checkpoint inhibitor; Drug therapy combination; Hypoxia; Immunology; Inflammation; Pancreatic cancer; Transforming growth factor β; Tumor microenvironment; Tumor-infiltrating lymphocyte.

Figure 1

Cytotoxic T lymphocyte-associated protein 4 and programmed cell death-1 biological functions and therapeutic targeting. Cells of the immune system express several surface molecules that are important for immune surveillance and regulation of the immune response. T cell receptor (TCR) is expressed by T cells; it is an antigen-specific molecule that is unique to each T cell clone. Major human compatibility (MHC) molecule is expressed by antigen-presenting cells (e.g., dendritic cell) and display a potential tumor antigen for recognition by the specific TCR. Left panel: When an antigen presented in the context of MHC is recognized by the TCR, interaction of CD28 (expressed by T cell) with B7 (CD80/CD86) molecules provide a co-stimulatory signal leading to T-cell activation. However, depending on the conditions and microenvironment, these T cells can also express various levels of cytotoxic T lymphocyte-associated protein 4 (CTLA-4), a regulatory receptor (immune checkpoint) with a higher binding affinity for B7 than CD28. Therefore, when CTLA-4 is available at the cell surface, it successfully competes for binding with B7, removing the co-stimulatory signal and leading to T-cell downregulation. Tumor cells can then escape the T cell cytotoxic effect (immune evasion). CTLA-4 blockade affects the immune priming phase occurring in the lymph node, by supporting the activation and proliferation of a higher number of effector T cells, regardless of TCR specificity, and by reducing Treg-mediated suppression of T-cell responses. Right panel: T cells also express PD-1 receptor, which has the potential to induce a programmed-death cascade in T cells that mistakenly react to host cells and thereby maintaining self-tolerance. PD-1 ligand, PD-L1, is used by tumor cells to engage the PD-1 receptor and switch off the reaction, inducing immune tolerance to the MHC-presented antigen. PD-L1 can also be expressed by stromal cells (e.g., M2 macrophages). PD-1 blockade works during the effector phase in peripheral tissues (tumor) to restore the immune function of “exhausted” T cells that have been turned off following extended or high levels of antigen exposure. CTLA-4: Cytotoxic T lymphocyte-associated protein 4; DC: Dendritic cell; MHC: Major human compatibility; PD-1: Programmed cell death-1; PD-L1: Programmed death-ligand 1; TCR: T cell receptor.

Figure 2

Summary of the mechanisms responsible for pancreatic ductal adenocarcinoma resistance to immune therapy. The circle outlines the three steps of the cancer-immunity cycle: (1) Immunogenicity (yellow); (2) T-cell recruitment and (3) activation. Pancreatic ductal adenocarcinoma resistance to immune therapy is due to the combination of several factors: (1) Low tumor immunogenicity, with a low mutation rate and low neaoantigen burden compared to other tumors (e.g., melanoma); (2) low T-cell recruitment and (3) activation: the dense desmoplastic stroma generates high interstitial pressure; this results in poor tumor perfusion and intra-tumor hypoxia, which in turn activates fibroblasts to release immunosuppressive cytokines (e.g., TGFβ, IL-6, CSF1 = “chemical barrier”) that lead to the recruitment of immunosuppressive cells (M2 macrophages, TREG, MDSC) and exclusion and anergy of effector T cells. CSF1: Colony stimulating factor 1; IL-6: Interleukin-6; MDSC: Myeloid-derived suppressive cells; TGFβ: Transforming growth factor β; TREG: T regulatory cells.