Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer.
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.
Evgeniy B
EB
Eruslanov
Pratik S
PS
Bhojnagarwala
Jon G
JG
Quatromoni
Tom Li
TL
Stephen
Anjana
A
Ranganathan
Charuhas
C
Deshpande
Tatiana
T
Akimova
Anil
A
Vachani
Leslie
L
Litzky
Wayne W
WW
Hancock
José R
JR
Conejo-Garcia
Michael
M
Feldman
Steven M
SM
Albelda
Sunil
S
Singhal
D015703:Antigens, CD / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology; D008297:Male; D009367:Neoplasm Staging; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D019707:Receptors, Chemokine / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
D015703:Antigens, CD; D016207:Cytokines; D019707:Receptors, Chemokine