Altered CD8+ t-cell lymphocyte function and tc1 cell stemness contribute to enhanced malignant tumor properties in murine models of sleep apnea

Abstract

Study Objective: The presence of obstructive sleep apnea (OSA) in patients with cancer appears to be accompanied by poorer outcomes. However, the mechanisms underlying such association are unknown. Tumor infiltrating lymphocytes (TILs), including CD8+ T cells, function as cytotoxic T lymphocytes (CTLs) and mount immune responses to cancer by the release of cytolytic enzymes, including granzyme B (GzmB), perforin (Prf), and cytokines such as interferon (IFN)-?. Methods: Using established in vivo mouse models, we investigated CD8+ T cells and cancer stem cells (CSCs) in intermittent hypoxia (IH) and sleep fragmentation (SF) in the context of tumor environment. Results: Both IH and SF promoted increased tumor growth and invasion toward adjacent tissues compared to controls. The number and frequency of GzmBproducing CD8+ T cells per milligram of tumor tissue was significantly reduced in IH-exposed mice with impaired cytolytic function in both the groups and correlated with tumor weight. We also found that Oct4+ and CD44+CD133+ expressing CSCs were considerably increased in IH and SF tumors, respectively. Conclusions: Reductions in GzmB in intratumoral CD8+ T cells in combination with the changes in tumor microenvironment that maintain the ability of CSCs to self-renew and even confer this capability to the nonstem population are compatible with reduced immunosurveillance and adverse tumor outcomes in animal models of OSA.