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+CD15hiCD10CD16lo 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.

Singhal S, Bhojnagarwala PS, O'Brien S, Moon EK, Garfall AL, Rao AS, et al. Origin and role of a subset of tumor-associated neutrophils with antigen-presenting cell features in early-stage human lung cancer. Cancer Cell 2016;30:120–35.