The Role of Immune Checkpoint Inhibitors in Metastatic Pancreatic Cancer: Current State and Outlook

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, characterized by its aggressive tumor biology and poor prognosis. While immune checkpoint inhibitors (ICIs) play a major part in the treatment algorithm of various solid tumors, there is still no evidence of clinical benefit from ICI in patients with metastatic PDAC (mPDAC). This might be due to several reasons, such as the inherent low immunogenicity of pancreatic cancer, the dense stroma-rich tumor microenvironment that precludes an efficient migration of antitumoral effector T cells to the cancer cells, and the increased proportion of immunosuppressive immune cells, such as regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and myeloid-derived suppressor cells (MDSCs), facilitating tumor growth and invasion. In this review, we provide an overview of the current state of ICIs in mPDAC, report on the biological rationale to implement ICIs into the treatment strategy of pancreatic cancer, and discuss preclinical studies and clinical trials in this field. Additionally, we shed light on the challenges of implementing ICIs into the treatment strategy of PDAC and discuss potential future directions.

Keywords: immune checkpoint inhibitors; metastatic; pancreatic cancer.

Figure 1

PDAC microenvironment with abundant cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM). The stroma impedes the infiltration of lymphocytes (Teffs), while the TME recruits various immunosuppressive immune cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory T cells (Tregs).

Figure 2

A selection of TME modulating agents and their inhibiting or activating effects on the TME components tested in mPDAC, either in preclinical models or clinical trials.