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

J Clin Invest. 2014 Dec;124(12):5466-80. doi: 10.1172/JCI77053. Epub 2014 Nov 10.

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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / immunology
  • Cell Proliferation*
  • Cytokines / immunology
  • Humans
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / pathology
  • Male
  • Neoplasm Staging
  • Neutrophil Activation*
  • Neutrophils / immunology*
  • Neutrophils / pathology
  • Receptors, Chemokine / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology

Substances

  • Antigens, CD
  • Cytokines
  • Receptors, Chemokine