Prognostic value of tumor-associated N1/N2 neutrophil plasticity in patients following radical resection of pancreas ductal adenocarcinoma

Abstract

BackgroundAs an integral part of the tumor microenvironment (TME), tumor-associated neutrophils play a crucial role in tumor development. The objective of this study was to investigate the plasticity of tumor-associated N1 and N2 neutrophils in the TME of pancreatic ductal adenocarcinoma (PDAC), along with its impact on survival and association with immune infiltrations.MethodsThe primary and validation cohorts including 90 radical resection patients from September 2012 to May 2016 and 29 radical resection patients from September 2018 to October 2019, respectively, with complete survival data, were enrolled. Immunofluorescence staining was used to identify tumor-associated N1 and N2 neutrophils, and the N1/N2 ratio was used to evaluate N1 and N2 plasticity. Thereafter, the association between tumor-associated N1/N2 neutrophil plasticity, clinical features, and immune infiltrations was investigated.ResultsThere was a significant increase in tumor-associated N2 neutrophils compared with tumor-associated N1 neutrophils. Low N1/N2 ratios were associated with the poorer differentiation of tumors, easier lymph node metastases, and a higher TNM stage. The median overall survival (OS) and recurrence-free survival (RFS) of the high tumor-associated N1 neutrophil group were significantly longer than those of the low group, while the tumor-associated N2 neutrophils played an opposite role. The multivariable analysis revealed that a high N1/N2 ratio was a significant prognostic indicator for OS and RFS. In addition, tumor-associated N1/N2 neutrophils showed an opposite correlation with tumor-infiltrating CD8+T cells and Tregs.ConclusionThe plasticity of tumor-associated N1/N2 neutrophils was identified as a crucial prognostic indicator that might reflect the TME and immune escape in patients with PDAC. On further investigation and validation, our findings may be used to further stratify patients with varying prognoses to optimize treatment.

Development of a Prognostic Model for Early Breast Cancer Integrating Neutrophil to Lymphocyte Ratio and Clinical-Pathological Characteristics

“…NLR reflects a broad interaction between systemic inflammation and overall immune function and may serve as a proxy for the equilibrium between tumor-mediated inflammation and antitumor immunity. 22 In multiple cancers, neutrophils accumulate in peripheral blood, and a high NLR has been positively associated with neutrophil infiltration into tumors 23 and worse immune status. 24 …”

Survival benefit and impact of adjuvant chemotherapy following systemic neoadjuvant chemotherapy in patients with resected pancreas ductal adenocarcinoma: a retrospective cohort study

“…For several decades, PDAC has been widely assumed to be curable only through surgical resection 3 . However, even with successful resection, the 5-year OS rate for patients is as low as 20%, and the median OS is only 24.1 months, which is significantly lower than the desired outcome 4 , 5 . Adjuvant chemotherapy (AC) with gemcitabine, oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) is currently being studied for PDAC, and reveals some efficacy 6 – 10 .…”

Poor clinical outcomes and immunoevasive contexture in CD161+CD8+T cells barren human pancreatic cancer

“…18 19 Immunofluorescence staining and evaluation Immunofluorescence staining was performed on the FFPE tissue specimens of the TMAs, as previously described. 19 During this process, anti-CD161 (Abcam, ab259916) and anti-CD8 (zsbio, ZA-0508) antibodies were applied, and the slides were incubated overnight at 4℃, then further incubated with Goat Anti-Rabbit IgG H&L (Abcam, ab205718), iFluor 488 tyramide (aatbio, 11060), and Alex Fluor594 donkey anti-rabbit IgG (Life, A32754). Subsequently, the slides were treated for 20 min with DAPI (Solarbio, #C0060).…”

“…Significant differences were observed in median OS and RFS between the high and low tumor-infiltrating CD8 + T cell groups (OS: 45.3 vs 22.3 months, p<0.001, HR=0.529, 95% CI 0.379 to 0.739, (online supplemental figure 2A); RFS: 25.3 vs 15.1 months, p=0.015, HR=0.665, 95% CI 0.483 to 0.915 (online supplemental figure 2B), which was consistent with our previous studies. 19 22 Notably, the high tumorinfiltrating CD161 + CD8 + T cell group showed significantly longer median OS and RFS compared with the low group (OS: 81.3 vs 19.2 months, p<0.001, HR=0.259, 95% CI 0.185 to 0.361, figure 1E; RFS: 41.4 vs 11.6 months, p<0.001, HR=0.357, 95% CI 0.259 to 0.490, figure 1F).…”