Cancer‐associated V‐ATPase induces delayed apoptosis of protumorigenic neutrophils

Tumors and neutrophils undergo an unexpected interaction, in which products released by tumor cells interact to support neutrophils that in turn support cancer growth, angiogenesis, and metastasis. A key protein that is highly expressed by cancer cells in tumors is the a2 isoform V‐ATPase (a2V). A peptide from a2V (a2NTD) is secreted specifically by cancer cells, but not normal cells, into the tumor microenvironment. This peptide reprograms neutrophils to promote angiogenesis, cancer cell invasiveness, and neutrophil recruitment. Here, we provide evidence that cancer‐associated a2V regulates the life span of protumorigenic neutrophils by influencing the intrinsic pathway of apoptosis. Immunohistochemical analysis of human cancer tissue sections collected from four different organs shows that levels of a2NTD and neutrophil counts are increased in cancer compared with normal tissues. Significant increases in neutrophil counts were present in both poorly and moderately differentiated tumors. In addition, there is a positive correlation between the number of neutrophils and a2NTD expression. Human neutrophils treated with recombinant a2NTD show significantly delayed apoptosis, and such prolonged survival was dependent on NF‐κB activation and ROS generation. Induction of antiapoptotic protein expression (Bcl‐xL and Bcl‐2A1) and decreased expression of proapoptotic proteins (Bax, Apaf‐1, caspase‐3, caspase‐6, and caspase‐7) were a hallmark of these treated neutrophils. Autocrine secretion of prosurvival cytokines of TNF‐α and IL‐8 by treated neutrophils prolongs their survival. Our findings highlight the important role of cancer‐associated a2V in regulating protumorigenic innate immunity, identifying a2V as a potential important target for cancer therapy.