Intratumoral CD56bright Natural Killer cells are associated with improved survival in bladder cancer

Abstract

Antitumor immune responses are largely mediated by cytotoxic lymphocytes that recognize tumor-associated antigens presented in the context of a major histocompatibility complex class I molecule (MHC I). However, many tumors downregulate MHC I expression as a means of immune escape. Under these conditions, additional effector lymphocytes, such as natural killer cells (NK cells) which mediate non-MHC restricted cytotoxicity, provide antitumor defenses. Using flow cytometric analysis, we discovered that NK cells predominate among lymphocytes infiltrating human and carcinogen-induced mouse bladder cancer (BC). Using transcriptomics and clinical outcomes from the TCGA dataset we found that the presence of intratumoral NK cells is associated with increased survival after cystectomy, especially in low MHC class I expressing tumors. We validated this finding using a local BC cohort and determined that functional NK cells decline with increasing patient age. Using in vitro assays, we found that intratumoral NK cells from bladder tumors exhibit MHC class I dependent cytotoxicity against BC cells. Importantly, intratumoral CD56dim NK cells increase with higher pathologic stage and are less functional (cytotoxicity and cytokine secretion) than CD56bright counterparts. The presence of intratumoral CD56brightNK cells predicts improved patient survival independent of tumor stage. We conclude that intratumoral NK cells are functional and prognostically relevant in BC, but their presence and function is diminished with aging or tumor MHC class I. Intratumoral CD56bright NK cells are associated with better clinical outcomes whereas CD56dim NK cells are dysfunctional and associated with advanced BC.