Human natural killer cells promote cross‐presentation of tumor cell‐derived antigens by dendritic cells

Dendritic cells (DCs) cross‐present antigen (Ag) to initiate T‐cell immunity against most infections and tumors. Natural killer (NK) cells are innate cytolytic lymphocytes that have emerged as key modulators of multiple DC functions. Here, we show that human NK cells promote cross‐presentation of tumor cell‐derived Ag by DC leading to Ag‐specific CD8⁺ T‐cell activation. Surprisingly, cytotoxic function of NK cells was not required. Instead, we highlight a critical and nonredundant role for IFN‐γ and TNF‐α production by NK cells to enhance cross‐presentation by DC using two different Ag models. Importantly, we observed that NK cells promote cell‐associated Ag cross‐presentation selectively by monocytes‐derived DC (Mo‐DC) and CD34‐derived CD11b^negCD141^high DC subsets but not by myeloid CD11b⁺ DC. Moreover, we demonstrate that triggering NK cell activation by monoclonal antibodies (mAbs)‐coated tumor cells leads to efficient DC cross‐presentation, supporting the concept that NK cells can contribute to therapeutic mAbs efficiency by inducing downstream adaptive immunity. Taken together, our findings point toward a novel role of human NK cells bridging innate and adaptive immunity through selective induction of cell‐associated Ag cross‐presentation by CD141^high DC, a process that could be exploited to better harness Ag‐specific cellular immunity in immunotherapy.