The tumor microenvironment may promote differentiation into immunostimulatory APC-like neutrophils.
Major finding: The tumor microenvironment may promote differentiation into immunostimulatory APC-like neutrophils.
Mechanism: IFNγ and GM-CSF downregulate Ikaros to promote differentiation of APC-like hybrid neutrophils.
Impact: Tumor-associated neutrophil subpopulations with specialized functions exist in human lung cancers.
Tumor-associated neutrophils (TAN) infiltrate and accumulate in multiple tumor types, including lung cancer. In mice, TANs have been reported to have both tumor-promoting and tumor-suppressing effects; however, there are limited data describing the phenotype and function of TANs in humans. A subpopulation of TANs in early-stage human lung cancer has been shown to express T-cell co-stimulatory molecules and stimulate T-cell responses, prompting Singhal and colleagues to hypothesize that early-stage tumors without fully developed immunosuppressive environments might promote differentiation of neutrophils into an antigen-presenting cell (APC)–like cell type. Consistent with this hypothesis, small size early-stage lung tumors accumulated a subset of TANs that exhibit hybrid characteristics of both neutrophils and APCs. This hybrid population disappeared as tumors enlarged. These APC-like hybrid TANs were fully functional and exhibited enhanced cytokine production and phagocytosis. Further, APC-like hybrid TANs efficiently stimulated T-cell responses compared with canonical TANs. Treatment of immature human bone marrow neutrophils (BMN) with tumor-conditioned media from tumors containing a high percentage of hybrid TANs resulted in a subset of CD11b+CD15hiCD10−CD16lo progenitor cells that gave rise to cells that recapitulated the hybrid TAN phenotype. The conditioned media that induced hybrid TANs had high levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon γ (IFNγ), which acted synergistically to downregulate Ikaros, a transcription factor involved in neutrophil differentiation, and promote the development of hybrid neutrophils. Unlike canonical neutrophils, the hybrid neutrophils enhanced T-cell production of IFNγ and Granzyme B, and effectively activated tumor-specific effector T cells. Moreover, the hybrid neutrophils were able to cross-present tumor-associated antigen as IgG immune complex. Taken together, these findings indicate that the tumor microenvironment in early-stage lung tumors can drive neutrophils to differentiate into a specialized cell subset with enhanced antitumor capabilities, and illustrate the diversity and plasticity of TANs.