Strategies for Increasing Pancreatic Tumor Immunogenicity

Abstract

Immunotherapy has changed the standard of care for multiple deadly cancers, including lung, head and neck, gastric, and some colorectal cancers. However, single-agent immunotherapy has had little effect in pancreatic ductal adenocarcinoma (PDAC). Increasing evidence suggests that the PDAC microenvironment is comprised of an intricate network of signals between immune cells, PDAC cells, and stroma, resulting in an immunosuppressive environment resistant to single-agent immunotherapies. In this review, we discuss differences between immunotherapy-sensitive cancers and PDAC, the complex interactions between PDAC stroma and suppressive tumor-infiltrating cells that facilitate PDAC development and progression, the immunologic targets within these complex networks that are druggable, and data supporting combination drug approaches that modulate multiple PDAC signals, which should lead to improved clinical outcomes. Clin Cancer Res; 23(7); 1656-69. ©2017 AACRSee all articles in this CCR Focus section, "Pancreatic Cancer: Challenge and Inspiration."

Figure 1. Mechanisms within the PDAC TME drives resistance to therapies

PDAC comprises of complex interactions between T cells, B cells, APCs, pancreatic tumor cells, and stromal elements. These interactions result in a profoundly immunosuppressive tumor microenvironment, and consequently single agent immunotherapy has been largely ineffective. However, emerging preclinical data has suggested that combination therapy may dramatically affect overall survival. Current trial design is being driven largely by this data. The figure summarizes major pathways in PDAC tumorigenesis that are being manipulated in clinical trials for patients with metastatic PDAC. Except for (G.), which represents in part IDO activated Tregs in TDLNs from a melanoma model (40), this figure represents data known exclusively from PDAC models. (A.) Tregs and γδ T cells block Teff division and drive PDAC growth, while γδ T cells block T cell infiltration (47). (B.) MDSCs and macrophages are mobilized into the TME by PDAC derived GM-CSF and CCL2, respectively. (145,183,184). (C.) Macrophages block CD4⁺ T cell entry into the PDAC microenvironment. CD40 is expressed on these CD4⁺ T cells, and activation of the CD40 pathway concurrently with gemcitabine can drive T cell infiltration (140). (D.) Stromal associated fibroblasts produce CXCL13, which recruits regulatory B cells into the TME. These regulatory B cells produce IL-35, which drives PDAC progression (136,185). These Bregs may be inhibited by BTK inhibitors, such as ibrutinib (137). (E.) Tumor infiltrating macrophages stimulate PDAC progression. Blockade of the CSF1 receptor expressed by macrophages can lead to macrophage depletion, CTLA-4 upregulation on CD8⁺ T cells, and PD-L1 upregulation on pancreatic tumor cells (146,147). (F.) Stromal elements create a physical barrier to immune infiltration and therapeutic agents. Stromal fibroblasts block Treg accumulation and PDAC progression (62), but targeting other stromal elements have achieved encouraging results. Stromal hyaluronic acid deposition results in decreased vascular patency (72,73), and FAK1 drives stromal fibrosis (68). Inhibition of either target has led to decreased PDAC progression when combined with chemotherapy in preclinical models. (G.) IDO induction in DCs by tumors activate Tregs via MHC and CTLA4 pathways (40,131). In phase II studies, gemcitabine based therapy synergizes with IDO inhibition to improve response rates in PDAC (133), possibly via transient depletion of Tregs (39). This provides an immune system reset, allowing for chemotherapy-mediated elimination of previously activated Tregs, followed by indoximod mediated inhibition of subsequent Treg activation. (H.) Recent evidence suggests the Fusobacterium found within the PDAC microenvironment drives PDAC progression, but the mechanism of this is unknown (91).

Figure 2. Therapeutic vaccine immunotherapy for PDAC requires multiple steps to overcome immunosuppression

PDAC and other poorly immune responsive cancers are characterized by low numbers of tumor infiltrating lymphocytes (TILs), low levels of PD-L1 expression, and high numbers of immunosuppressive cells such as Tregs and MDSCs at baseline (left panel) (13). Using a vaccine approach will require at least two immunotherapeutics to achieve an immune response. In Step 1 (center panel), a therapeutic vaccine is used to induce accumulation of lymphoid aggregates (35). These lymphocytes secrete interferon gamma and other soluble factors that induce high levels of PD-L1/PD-1 expression on epithelial tumor cells and on immune cells (186). Vaccines can also be combined with other therapies such as cyclophosphamide, to deplete immunosuppressive cells in the TME (29). In Step 2 (right panel), the addition of a PD-pathway inhibitor to a vaccine-primed tumor inhibits PD-L1/PD-1 signaling to increase lymphocyte proliferation and activation and promote tumor eradication (36). The hypothesis that vaccine therapy can synergize with immune checkpoint inhibition is currently under clinical investigation in multiple trials in PDAC.