Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer‑associated fibroblasts

Takesue, Shin; Ohuchida, Kenoki; Shinkawa, Tomohiko; Otsubo, Yoshiki; Matsumoto, Sokichi; Sagara, Akiko; Yonenaga, Akiko; Ando, Yuichi; Kibe, Shin; Nakayama, Hiromichi; Iwamoto, Chika; Shindo, Koji; Moriyama, Taiki; Nakata, Kohei; Miyasaka, Yoshihiro; Ohtsuka, Takao; Toma, Hiroki; Tominaga, Yoshihiro; Mizumoto, Kazuhiro; Hashizume, Makoto; Nakamura, Masafumi

doi:10.3892/ijo.2019.4951

Cited by 52 publications

(50 citation statements)

References 42 publications

(50 reference statements)

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“…These results identify the immunosuppressive phenotypes of liver metastatically infiltrated P2RX1-deficient neutrophils. Neutrophil extracellular traps (NETs) in promoting tumor metastasis have attracted much attention recently 22,[32][33][34] . We observed that NETs were substantially generated in liver metastases, but no significant differences were seen between WT and P2rx1 −/− mice ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of a subset of immunosuppressive P2RX1-negative neutrophils in pancreatic cancer liver metastasis

Wang

Qin

et al. 2021

Nat Commun

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The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils.

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Section: Resultsmentioning

confidence: 99%

Identification of a subset of immunosuppressive P2RX1-negative neutrophils in pancreatic cancer liver metastasis

Wang

Qin

et al. 2021

Nat Commun

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“…Another important mechanism involves neutrophil extracellular traps (NETs), fibrillar structures, secreted by neutrophils under the effect of various stimulating factors and involved in the innate immune response (50,51). Many recent studies have shown that in addition to the innate immune response, NETs initiate and promote tumor progression and metastasis via several mechanisms (52)(53)(54). NETs are composed of depolymerized chromatin and different protein particles, including a loose DNA skeleton, matrix metalloproteinase-9 (MMP-9), neutrophil elastase (NE), cathepsin G (CG), and myeloperoxidase (50).…”

Section: Discussionmentioning

confidence: 99%

Elevated Neutrophil-to-Lymphocyte Ratio Is Associated With Poor Outcomes for Melanoma Patients Treated With PD-1 Inhibitor or Chemotherapy in a Chinese Population

Qi¹,

Liao²,

Mei³

et al. 2020

Front. Oncol.

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Background: Previous studies have suggested that an elevated pre-treatment neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in patients with a variety of cancers. The purpose of this retrospective analysis is to investigate the prognostic value of the NLR in a Chinese melanoma population. Methods: Melanoma patients were divided into two groups based on pre-treatment NLR values (≥3 vs. <3). Cox proportional hazard regression analysis and the Kaplan-Meier method were employed to study the prognostic role of the NLR for overall survival (OS) and progression-free survival (PFS). Results: A total of 159 melanoma patients were included in this study, including 40 patients treated with PD-1 inhibitor and 119 patients treated with chemotherapy. In the PD-1 inhibitor group, the median OS was 18.0 months in the low NLR subgroup and 5.6 months in the high NLR subgroup; the median PFS was 7.0 and 2.2 months, respectively. In chemotherapy group, the median OS was 23.0 months in the low NLR group and 8.0 months in the high NLR group, and the median PFS was 9.0 and 4.0 months, respectively. Multivariate analysis showed that the NLR was significantly associated with OS and PFS in melanoma patients treated with either PD-1 inhibitor immunotherapy or chemotherapy. Conclusion: In the Chinese population, an elevated NLR was closely related to worse survival in patients with melanoma treated with either PD-1 inhibitor monotherapy or chemotherapy.

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“…The formation of NETs or NETosis is another pro-cancer and pro-metastatic activity of neutrophils [ 45 ]. NETs or NETosis is a newly identified form of neutrophil cell death that has been shown to play a pivotal role in cancer progression and facilitating metastasis [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Breast Cancer Cell–Neutrophil Interactions Enhance Neutrophil Survival and Pro-Tumorigenic Activities

Saxena

Goel

et al. 2020

Cancers

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Breast cancer remains the most prevalent cancer in women with limited treatment options for patients suffering from therapy-resistance and metastatic disease. Neutrophils play an important role in breast cancer progression and metastasis. We examined the pro-tumorigenic nature of the breast cancer cell–neutrophil interactions and delineated the differences in neutrophil properties between the chemotherapy-resistant and the parent tumor microenvironment. Our data demonstrated that high neutrophil infiltration is associated with disease aggressiveness and therapy resistance. In the human breast cancer dataset, expression of neutrophil-related signature gene expression was higher in tumors from therapy-resistant patients than therapy-sensitive patients. We observed that breast cancer-derived factors significantly enhanced neutrophil survival, polarization, and pro-inflammatory cytokine expression. Breast cancer cell-derived supernatant treated neutrophils significantly expressed high levels of interleukin-1β (IL-1β), CC-chemokine ligand-2-4 (CCL2, CCL3, CCL4), inducible nitric oxide synthase (iNOS), and matrix metallopeptidase-9 (MMP9), and formed extracellular traps (NETs). Moreover, neutrophils showed increased secretion of MMP9 when cultured with the supernatant of chemotherapy-resistant Cl66-Doxorubicin (Cl66-Dox) and Cl66-Paclitaxel (Cl66-Pac) cells in comparison with the supernatant of Cl66-parent cells. Together, these data suggest an important role of breast cancer cell–neutrophil interactions in regulating pro-tumor characteristics in neutrophils and its modulation by therapy resistance.

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Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer‑associated fibroblasts

Cited by 52 publications

References 42 publications

Identification of a subset of immunosuppressive P2RX1-negative neutrophils in pancreatic cancer liver metastasis

Identification of a subset of immunosuppressive P2RX1-negative neutrophils in pancreatic cancer liver metastasis

Elevated Neutrophil-to-Lymphocyte Ratio Is Associated With Poor Outcomes for Melanoma Patients Treated With PD-1 Inhibitor or Chemotherapy in a Chinese Population

Breast Cancer Cell–Neutrophil Interactions Enhance Neutrophil Survival and Pro-Tumorigenic Activities

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