PGE ₂ expression by HPV6/11‐induced respiratory papillomas blocks NK cell activation in patients with recurrent respiratory papillomatosis

Recurrent respiratory papillomatosis (RRP), a rare chronic disease caused primarily by human papillomavirus types 6 and 11, consists of repeated growth of premalignant papillomas in the airway. RRP is characterized by multiple abnormalities in innate and adaptive immunity. Natural killer (NK) cells play important roles in immune surveillance and are part of the innate immune responses that help prevent tumor growth. We identified that papillomas lack classical class I MHC and retain nonclassical class I MHC expression. Moreover, in this study, we have identified and characterized the mechanism that blocks NK cell targeting of papilloma cells. Here, we show for the first time that the PGE 2 secreted by papilloma cells directly inhibits NK cells activation/degranulation principally through the PGE 2 receptor EP2, and to a lesser extent through EP4 signaling. Thus, papilloma cells have a potent mechanism to block NK cell function that likely supports papilloma cell growth.