Intratumoral CD56bright natural killer cells are associated with improved survival in bladder cancer

Abstract

Background: Natural killer (NK) cells are effective at killing tumors in a non-MHC restricted manner and are emerging targets for cancer therapy but their importance in bladder cancer (BC) is poorly defined. NK cells are commonly subdivided into populations based on relative surface expression of CD56. Two major subsets are CD56^bright and CD56^dim NK cells.

Methods: The prevalence of intratumoral lymphocytes was examined via flow cytometric analysis of bladder tissue from a local cohort of patients with non-invasive and invasive BC (n=28). The association of NK cell subsets with cancer-specific survival (CSS) and overall survival (OS) was examined in 50 patients with BC using Cox regression. Fluorescence-activated cell sorting (FACS) of intratumoral lymphocytes isolated CD56 NK cell subsets were used for examination of function, including cytokine production and in vitro cytotoxicity.

Results: NK cells predominated among bladder intratumoral lymphocytes. Intratumoral CD56^bright NK cells showed increased cytokine production and cytotoxicity compared to their CD56^dim counterparts and were associated with improved CSS and OS independent of pathologic tumor stage. On the other hand, CD56^dim NK cells were not associated with improved outcomes but were associated with higher pathologic stage.

Conclusions: NK cells are frequent among intratumoral lymphocytes in BC. Bladder intratumoral CD56^bright NK cells are functional and prognostically relevant whereas CD56^dim NK cells are dysfunctional and prevalent in higher stage tumors. Thus, CD56^bright NK cells are promising targets in BC.

Keywords: CD56; NK cells; bladder cancer; survival; tumor-infiltrating lymphocytes.