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.

Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer

“…Multiple hypotheses may explain why pancreatic cancer has not responded well to various immunotherapy treatments (20-23). One major hypothesis relates to the dense stroma within the TME (24). Preclinical observations have suggested that because of the presence of a complex desmoplastic stroma, immune cells-particularly T cellscannot infiltrate the TME (25,26).…”

Autophagy as a therapeutic target in pancreatic cancer

“…As previously mentioned, the activity of programmed cell death 1 receptor (PD-1)/programmed cell death ligand 1 (PD-L1)-and cytotoxic T-lymphocyte-associated protein 4 (CTLA4)-blocking agents against PDAC is limited and the activity of novel combinations of immunotherapeutic agents reported so far has been at best disappointingly low in patients with microsatellite stable PDAC. 55,56 The outcome of autophagy modulation to treat cancer is the result of a complex combination of the effect of autophagy on tumour cells and cells of the microenvironment, which includes immune cells. In addition, the interaction of various cell populations such as macrophages and fibroblasts, which both play a critical role in the immune context of PDAC, and T cells, renders deciphering the exact role of autophagy even more challenging.…”

Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status and future prospects

“…For esophageal cancer, several clinical trials, which evaluate the combination of chemoradiotherapy with ICIs as neoadjuvant or first-line treatment are now ongoing ( Table 2). ICI monotherapy activity was not observed in advanced pancreatic cancer patients due to the low immunogenicity and lymphocyte infiltration of tumor lesions [87]. To reverse the immunosuppression of pancreatic cancer, the combination of ICIs with cytotoxic agents, including gemcitabine, irinotecan, 5-FU, and albumin-bound paclitaxel is being evaluated by clinical trials.…”