Hypoxia, a Targetable Culprit to Counter Pancreatic Cancer Resistance to Therapy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and it is a disease of dismal prognosis. While immunotherapy has revolutionized the treatment of various solid tumors, it has achieved little success in PDAC. Hypoxia within the stroma-rich tumor microenvironment is associated with resistance to therapies and promotes angiogenesis, giving rise to a chaotic and leaky vasculature that is inefficient at shuttling oxygen and nutrients. Hypoxia and its downstream effectors have been implicated in immune resistance and could be contributing to the lack of response to immunotherapy experienced by patients with PDAC. Paradoxically, increasing evidence has shown hypoxia to augment genomic instability and mutagenesis in cancer, suggesting that hypoxic tumor cells could have increased production of neoantigens that can potentially enable their clearance by cytotoxic immune cells. Strategies aimed at relieving this condition have been on the rise, and one such approach opts for normalizing the tumor vasculature to reverse hypoxia and its downstream support of tumor pathogenesis. An important consideration for the successful implementation of such strategies in the clinic is that not all PDACs are equally hypoxic, therefore hypoxia-detection approaches should be integrated to enable optimal patient selection for achieving improved patient outcomes.

Keywords: ITPP; genomic instability; hypoxia; hypoxia detection; hypoxia signature; immunotherapy; pancreatic cancer; targeting hypoxia; tumor mutational burden; vascular normalization.

Figure 1

Hypoxia-mediated effects affecting various processes of tumors and the tumor microenvironment. ITPP, myo-inositol-trispyrophosphate; ROS, reactive oxygen species.

Figure 2

Vascular normalization to restore the anti-tumor immune response in PDAC. Vascular normalization is expected to reverse the immunosuppressive tumor microenvironment, thus enabling response to immune checkpoint inhibitors (ICIs). In addition, the effect of hypoxia on increased tumor mutational burden (TMB) and genomic instability could potentially increase the production of neoantigens. The uptake of such foreign antigens and their presentation to T cells could then enable tumor-cell killing.