Effects of Hypoxia-induced Extracellular Matrix Remodeling in Immune Responses in Ovarian Cancer — 47p — Simona Plesselova¹, Pilar de la Puente¹

1. Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD

Ovarian cancer (OC) is characterized by late diagnosis, drug resistance, and immune evasion with a poor survival rate. Hypoxia (low oxygen levels) is one of the hallmarks of OC that can induce an immunologically cold tumor microenvironment (TME) either by over-expression of immunosuppressive molecules in tumor cells or by affecting the activity of the immune cells. Also, hypoxia induces extracellular matrix (ECM) remodeling in the TME caused by cancer-associated fibroblasts (CAFs) by secreting higher concentration of collagens mediated through the TGF-β pathway.  that acts as a physical obstacle to immune infiltration. Paradoxically, the presence of tumor-infiltrated lymphocytes in OC was correlated with better patient outcomes. Moreover, current studies compare the hypoxic TME (1.5% O₂) with hyperoxic models (21% O₂) although the physiologically relevant oxygen levels in the healthy ovary are 5-10%, therefore new physiologically relevant preclinical models are needed.

We have bio-engineered a patient-derived 3D model to study the role of hypoxia-induced ECM remodeling in TME-immune interactions. We have shown that in the hypoxic TME, compared to physoxia, there was a higher collagen I deposition due to CAFs and ECM stiffness that significantly impaired lymphocyte infiltration. Moreover, hypoxia induced higher expression of immunosuppressive markers in cancer cells, but conversely, also higher activation and cytotoxic capacity of CD8+ T cells. Furthermore, we have demonstrated that targeting hypoxia-induced ECM remodeling can overcome impaired T cell infiltration. Thus, hypoxia is a “friend and foe” for OC, as it enhances the activation and cytotoxic function of T cells but also induces an immunosuppressive TME and impairs immune infiltration by ECM-remodeling and can be targeted to improve immunotherapy efficacy and OC patient outcomes.

Sanford Research
Pilar De la Puente