Pancreatic Cancer and Immunotherapy: A Clinical Overview

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC's immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.

Keywords: ablation; adoptive cell therapy; cancer vaccine; immunomodulators; immunotherapy; oncolytic virus; pancreatic cancer.

Figure 1

The immune evasion mechanisms of pancreatic cancer. (1a) Tumor cells release a plethora of immune-suppressive, pro-tumorigenic cytokines (e.g., IL-6, IL-8, IL-10, TGF-β, M-CSF and VEGF) and chemokines (e.g., CXCL12) into the microenvironment, which (1b) attract and activate immune-suppressive cells (including Tregs, MDSCs, TAMs and CAFs), subsequently resulting in (1c) exclusion of immune permissive anti-tumor cells (including Th1 CD4⁺ cells, CD8⁺ T cells, DCs and NK cells). (2) Tumor cells upregulate co-inhibitory receptors, or immune checkpoints, such as PD-L1, CD155/112 and Gal-9, to impede an anti-tumor T cell response. (3) Tumor-induced CAFs modulate the extracellular matrix, promoting fibrotic reformation, leading to a desmoplastic stroma which acts as a physical barrier for anti-tumor immune cells and systemic treatments. (4) Tumor cells increase their apoptotic resistance through augmented expression of apoptotic regulatory proteins STAT3 and BCL-2. Reduced immune recognition is established by its low mutational burden and through downregulation of MHC-I membrane proteins.

Figure 2

Immune checkpoint inhibitors anti-CTLA-4, anti-PD1 and anti-PD-L1. During the priming phase (in the lymph nodes), T cell priming may be inhibited, even though they are presented with antigen-loaded MHC complexes, through binding of CD80 or CD86 on dendritic cells (DCs) with CTLA-4 on naïve T cells. Anti-CTLA-4 antibodies block this interaction, reversing T cell inhibition, prompting activation and expansion of antigen-specific effector T cells. During the effector phase (at the tumor site), T cell inhibition can be established through PD-1 ligation (T cells) with PD-L1 (tumor and myeloid cells). This process can be reversed by using anti-PD-1 or anti-PD-L1 antibodies, allowing CD8⁺ T cell-induced killing of tumor cells. Of note, recent studies also point to decreases in suppressive Treg rates and decreased T cell priming by CD28 signaling interference upon CTLA-4 and PD-1 blockade, respectively.

Figure 3

Adjuvants. Toll-like receptor (TLR) agonists bind onto transmembrane or intracellular TLRs and stimulator of interferon (IFN) genes (STING) agonists activate the intracellular cyclic GMP-AMP synthase (cGAS)-STING pathway in immature dendritic cells (DCs). Both agonists prompt release of pro-inflammatory cytokines, including type 1 IFN. These IFNs activate other DCs, effector T cells and natural killer (NK) cells.

Figure 4

Oncolytic viral therapy. Oncolytic viruses may be equipped with a transgene (e.g., immune checkpoint inhibitor (ICI) or cytokine), creating an armed oncolytic virus. Oncolytic viruses can be administered intravenously or intratumorally and will infect both healthy cells and tumor cells. In the former, viruses are cleared, whereas in the latter, due to activation of oncogenic pathways and a defective interferon (IFN) response, oncolytic viruses thrive, leading to production of novel viral particles to a point where the cell lyses due to viral overload. Newly created oncolytic viruses, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and tumor antigens are released into the microenvironment. New waves of released oncolytic viruses can then infect other tumor cells. Dendritic cells (DCs) take up, process and present the released antigens and upon activation by the released DAMPs and PAMPs via their pattern recognition receptors (PRRs), will transport them to the draining lymph nodes where T cell priming takes place. Primed effector T cells (Th1 CD4⁺, CD8⁺) subsequently provide systemic immune surveillance and will migrate towards the original tumor site (but also to distant, uninjected metastatic sites) via a chemokine gradient, often provided by activated DCs.

Figure 5

Adoptive cell therapy. Allogeneic (donor) or autologous (patient) blood can be used to isolate T cells or NK cells. Similarly, autologous tumor tissue can be collected to isolate tumor-infiltrating lymphocytes (TILs), generally T cells. These isolated cells are cultured in vitro and can be selected for expansion based on their anti-tumoral capacity or enhanced with T cell receptors (TCRs) or chimeric antigen receptors (CARs). Following in vitro manipulation and stimulation and, in case of systemic administration, subsequent to a lymphodepleting chemo(radio)therapy regimen, these cells are injected intratumorally (i.t.) or intravenously (i.v.) to (systemically) detect and kill cancer cells.

Figure 6

Cancer vaccines and in vivo vaccination following chemotherapy, ablation or oncolytic viral therapy. Cancer vaccines: Peptide-based vaccines can be produced on the basis of a patient’s mutational profile (i.e., KRAS (or other) neoantigens) or using (a combination of) generic tumor-associated antigens (TAAs). Whole-tumor-cell vaccines can be generated with autologous tumor lysate or using (a combination of) allogeneic PDAC cell lines. Peptide vaccines and whole-tumor-cell vaccines may be supplemented with cytokines, such as granulocyte macrophage colony-stimulating factor (GM-CSF), or adjuvants, which attracts and activates dendritic cells (DCs). For DC vaccines, autologous or allogeneic DCs are generated in vitro from patient or donor derived precursors in blood (e.g., monocytes), followed by antigen pulsing. Cancer vaccines may be administered intratumorally, intravenously, intranodally or subcutaneously, intradermally or intramuscularly. In vivo vaccination: Chemotherapy, oncolytic viruses and local ablative treatments (e.g., stereotactic ablative body radiotherapy (SABR) and irreversible electroporation (IRE)) have the capacity to initiate immunogenic cell death, thereby releasing damage-associated molecular patterns (DAMPs) and antigens, followed by alleviation of tumor-induced immune suppression and tumor-specific T cell priming. The immune response may be further leveraged by employing other immunotherapies such as immune checkpoint inhibitors (ICI), adoptive cell therapies (ACT) or adjuvants. Systemic immune response: With the exception of antigen-pulsed DC vaccines, all other forms of vaccination require in vivo antigen uptake of DCs. Activated DCs transport the antigens to the draining lymph nodes and establish antigen-specific priming and expansion of T cells. Primed effector anti-tumor T cells (Th1 CD4⁺ and CD8⁺ cytolytic T cells) roam the system in search of tumor cells and upon discovery may destroy these cancerous cells.