Pancreatic Ductal Adenocarcinoma: A Strong Imbalance of Good and Bad Immunological Cops in the Tumor Microenvironment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers with very few available treatments. For many decades, gemcitabine was the only treatment for patients with PDAC. A recent attempt to improve patient survival by combining this chemotherapy with FOLFIRINOX and nab-paclitaxel failed and instead resulted in increased toxicity. Novel therapies are urgently required to improve PDAC patient survival. New treatments in other cancers such as melanoma, non-small-cell lung cancer, and renal cancer have emerged, based on immunotherapy targeting the immune checkpoints cytotoxic T-lymphocyte-associated antigen 4 or programmed death 1 ligand. However, the first clinical trials using such immune checkpoint inhibitors in PDAC have had limited success. Resistance to immunotherapy in PDAC remains unclear but could be due to tissue components (cancer-associated fibroblasts, desmoplasia, hypoxia) and to the imbalance between immunosuppressive and effector immune populations in the tumor microenvironment. In this review, we analyzed the presence of "good and bad immunological cops" in PDAC and discussed the significance of changes in their balance.

Keywords: hypoxia; immune checkpoint; immune infiltrate; immunosuppression; pancreatic ductal adenocarcinoma; tumor microenvironment.

Figure 1

Evolution of the immune cell population and pancreatic ductal adenocarcinoma (PDAC) development through the three Es of cancer immunoediting. During cancer immunosurveillance (1), immune effector cells M1 macrophages and N1 neutrophils are recruited to the tissue in order to eliminate heterogenic mutant/tumor cells. While these immune cells kill most tumor cells, specific resistant tumor clones (in dark blue) survive (2). An equilibrium between anti- and pro-tumor immune cells is maintained until tumor cells and immunosuppressive immune cells develop tumor escape mechanisms via the secretion of pro-tumor factors (IL-10, TGF-β, etc.) and inhibitory co-signaling molecules (3). Tumor escape induces the growth of tumor cells, angiogenesis, metastasis, the establishment of an immunosuppressive microenvironment with the presence of Tregs, tumor-associated macrophages (TAMs) such as M2, CAFs, myeloid-derived suppressive cells (MDSCs), tumor-associated neutrophils (TANs) such as N2 and with hypoxia and desmoplasia, which increase the pro-tumor impact and create a barrier (high blood pressure) against therapeutic drug delivery and recruitment of effector immune cells. M1: anti-tumor macrophages, M2: pro-tumor macrophages, N1: anti-tumor neutrophils, N2: pro-tumor neutrophils, CD8: CD8⁺ T cells, Th1/Th2: CD4⁺ Th1 (anti-tumor) or Th2 (pro-tumor) T cells, Treg: regulatory T cells, CAFs: cancer-associated fibroblasts.

Figure 2

Pancreatic ductal adenocarcinoma (PDAC) development induces the shift of pro-inflammatory to immunosuppressive immune populations. At early PDAC stages, a primarily anti-tumor immune population favors the effector T-cell functions of such as CD8⁺ and natural killer (NK) cells toward the prevention of tumor cell growth. Despite this initial anti-tumor response, over time chronic activation of these effector immune cells brings about a smoldering inflammation process that selects resistant tumor clones resulting in the promotion and development of immunosuppressive immune populations under hypoxic stress.