Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer

TLDR

In the tumor microenvironment, inflammatory cells are abundant, yet the specific roles of tumor‑associated neutrophils (TANs) remain largely unknown. This study aimed to phenotypically and functionally characterize TANs from surgically resected lung cancer patients. TANs comprised 5–25 % of tumor cells, displayed an activated phenotype, produced pro‑inflammatory cytokines, and, unlike blood neutrophils, stimulated T‑cell proliferation and IFN‑γ release, establishing a positive‑feedback loop that indicates TANs promote rather than suppress early‑stage lung‑cancer immunity.

Abstract

Infiltrating inflammatory cells are highly prevalent within the tumor microenvironment and mediate many processes associated with tumor progression; however, the contribution of specific populations remains unclear. For example, the nature and function of tumor-associated neutrophils (TANs) in the cancer microenvironment is largely unknown. The goal of this study was to provide a phenotypic and functional characterization of TANs in surgically resected lung cancer patients. We found that TANs constituted 5%-25% of cells isolated from the digested human lung tumors. Compared with blood neutrophils, TANs displayed an activated phenotype (CD62L(lo)CD54(hi)) with a distinct repertoire of chemokine receptors that included CCR5, CCR7, CXCR3, and CXCR4. TANs produced substantial quantities of the proinflammatory factors MCP-1, IL-8, MIP-1α, and IL-6, as well as the antiinflammatory IL-1R antagonist. Functionally, both TANs and neutrophils isolated from distant nonmalignant lung tissue were able to stimulate T cell proliferation and IFN-γ release. Cross-talk between TANs and activated T cells led to substantial upregulation of CD54, CD86, OX40L, and 4-1BBL costimulatory molecules on the neutrophil surface, which bolstered T cell proliferation in a positive-feedback loop. Together our results demonstrate that in the earliest stages of lung cancer, TANs are not immunosuppressive, but rather stimulate T cell responses.