Tumor Related Neutrophils - A New Challenge in Cancer Immunology and Immunotherapy

A significant portion of the inflammatory cell infiltrate in cancer is consist of neutrophils. During the last years, we and others have published several studies challenging the limited view of neutrophils as short-acting phagocytic cells. We demonstrated that Tumor associated neutrophils (TAN) can have a dual role in tumor biology, polarized by the tumor microenvironment to have either anti-tumorigenic (‘N1’) or pro-tumorigenic (‘N2’) functions. Circulating neutrophils in cancer have been shown to be capable of direct tumor cytotoxicity. N1/N2 TAN differ from each other, from naïve neutrophils (NN) and from the granulocytic fraction of MDSC (G-MDSC), with many immune-related genes/pathways up-regulated in TAN. In a recent study, we identified a heterogeneous subset of circulating low-density neutrophils (LDN) that accumulate continuously with cancer progression. LDN display impaired neutrophil function and immunosuppressive properties, in stark contrast to those of mature, high-density neutrophils (HDN). Importantly, LDN consist of both immature MDSC and mature cells derived from HDN. In additional work we found several links between tumor neutrophils and the adaptive immune system affecting the immune microenvironment. TAN are capable of recruiting regulatory T-cells into the tumor by secretion of CCL17, and currently we are investigating their capability to induce apoptosis of CD8⁺ T-cells. Our findings provide a mechanistic explanation to mitigate the controversy surrounding neutrophil functions in cancer. Proper understanding of the effect of tumors on neutrophils, as well as the way these cells support or fight cancer and affect tumor immune microenvironment, will help us develop strategies to direct the immune system against the tumor. Our long term goal is to promote cancer treatment using manipulated neutrophils as a novel tool to treat advanced cancer and metastases.