Using samples from cetuximab + radiochemotherapy-treated clinical trial patients with pancreatic cancer, Walle et al. showed that NK cells egressed from peripheral blood, and CXCL8 (IL-8) levels increased in serum; both correlated with patient survival. Radiotherapy (RT) induced CXCR1/2+CD56dim NK cell accumulation in resected tumors from an independent cohort, and NF-kB/mTOR regulated CXCL8 release from senescing tumor cells in vitro. In a mouse xenograft model, RT induced human NK cell infiltration toward, and CXCL8 release from human tumor cells. Combining adoptive human NK cell transfer with RT enhanced antitumor activity.
Contributed by Paula Hochman
ABSTRACT: Radiotherapy is a mainstay cancer therapy whose antitumor effects partially depend on T cell responses. However, the role of Natural Killer (NK) cells in radiotherapy remains unclear. Here, using a reverse translational approach, we show a central role of NK cells in the radiation-induced immune response involving a CXCL8/IL-8-dependent mechanism. In a randomized controlled pancreatic cancer trial, CXCL8 increased under radiotherapy, and NK cell positively correlated with prolonged overall survival. Accordingly, NK cells preferentially infiltrated irradiated pancreatic tumors and exhibited CD56dim-like cytotoxic transcriptomic states. In experimental models, NF-κB and mTOR orchestrated radiation-induced CXCL8 secretion from tumor cells with senescence features causing directional migration of CD56dim NK cells, thus linking senescence-associated CXCL8 release to innate immune surveillance of human tumors. Moreover, combined high-dose radiotherapy and adoptive NK cell transfer improved tumor control over monotherapies in xenografted mice, suggesting NK cells combined with radiotherapy as a rational cancer treatment strategy.