Immune Checkpoint Inhibition for Pancreatic Ductal Adenocarcinoma: Current Limitations and Future Options

Abstract

Pancreatic ductal adenocarcinoma (PDAC), as the most frequent form of pancreatic malignancy, still is associated with a dismal prognosis. Due to its late detection, most patients are ineligible for surgery, and chemotherapeutic options are limited. Tumor heterogeneity and a characteristic structure with crosstalk between the cancer/malignant cells and an abundant tumor microenvironment (TME) make PDAC a very challenging puzzle to solve. Thus far, targeted therapies have failed to substantially improve the overall survival of PDAC patients. Immune checkpoint inhibition, as an emerging therapeutic option in cancer treatment, shows promising results in different solid tumor types and hematological malignancies. However, PDAC does not respond well to immune checkpoint inhibitors anti-programmed cell death protein 1 (PD-1) or anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) alone or in combination. PDAC with its immune-privileged nature, starting from the early pre-neoplastic state, appears to escape from the antitumor immune response unlike other neoplastic entities. Different mechanisms how cancer cells achieve immune-privileged status have been hypothesized. Among them are decreased antigenicity and impaired immunogenicity via both cancer cell-intrinsic mechanisms and an augmented immunosuppressive TME. Here, we seek to shed light on the recent advances in both bench and bedside investigation of immunotherapeutic options for PDAC. Furthermore, we aim to compile recent data about how PDAC adopts immune escape mechanisms, and how these mechanisms might be exploited therapeutically in combination with immune checkpoint inhibitors, such as PD-1 or CTLA-4 antibodies.

Keywords: antigenicity; immune checkpoint inhibitors; immunogenicity; pancreatic ductal adenocarcinoma; triple E; tumor microenvironment.

Figure 1

Conventional triple E hypothesis: elimination, equilibrium, and escape. While many solid tumors responding to ICI therapy follow triple E of immunoediting, PDAC is mostly an exception. Generated new clones due to Darwinian-like selection reduce their antigenicity and immunogenicity, escaping from immunosurveillance. Abbreviations: M, macrophages; NK, natural killer; NKT, natural killer T cells; CTLs, cytotoxic T lymphocytes; N, neutrophils; M2, M2 phenotype macrophages; MDSCs, myeloid-derived suppressor cells; T_reg, regulatory T cells; CAFs, cancer-associated fibroblasts; ICI, immune checkpoint inhibition.

Figure 2

Immunoediting in PDAC: only tumors with genetic instability follow Triple E, while others cannot. Immunosuppressive TME blocks initial CTL priming. Therefore, cancer cells are not forced to undergo Darwinian-like selection. PDAC can still retain its antigenic capacity while impairing immunogenicity making it unresponsive to checkpoint inhibitors. Abbreviations: CTLs, cytotoxic T lymphocytes; N, neutrophils; M2, M2 phenotype macrophages; MDSCs, myeloid-derived suppressor cells; T_regs, regulatory T cells; CAFs, cancer-associated fibroblasts; γδT, γδT cells; MMR, mismatch repair; MSI, microsatellite instability; TME, tumor microenvironment.

Figure 3

Factors determining ICI efficiency in PDAC: while modulation of antigenicity, intrinsic immunogenicity, and extrinsic immunogenicity via TME might be valid for many tumors, drawn examples above are experimentally shown for PDAC. Abbreviations: TAAs, tumor-associated antigens; TSAs, tumor-specific antigens; CTLs, cytotoxic T lymphocytes; N, neutrophils; M2, M2 phenotype macrophages; MDSCs, myeloid-derived suppressor cells; T_regs, regulatory T cells; CAFs, cancer-associated fibroblasts; γδT, γδT cells; MMR, mismatch repair; MSI, microsatellite instability; TME, tumor microenvironment; ICI, immune checkpoint inhibition.

Figure 4

Combination therapeutic options to increase ICI efficiency: while given therapeutic options are placed in the corresponding cluster, only published data thus far are taken into consideration. This still does not eliminate their potential to affect other aspects. While treatments focusing on a single aspect (either one of antigenicity/intrinsic immunogenicity/TME modulation) might be effective, the best synergism will probably be achieved through combinations focusing on all aspects. Abbreviations: ICI, immune checkpoint inhibition, DDR, DNA damage response.