title: Myeloid clusters are associated with a pro-metastatic environment and poor prognosis in smoking-related early stage non-small cell lung cancer.
abstract: BACKGROUND
  This study aimed to understand the role of myeloid cell clusters in uninvolved regional lymph nodes from early stage non-small cell lung cancer patients.
  
  
  METHODS
  Uninvolved regional lymph node sections from 67 patients with stage I-III resected non-small cell lung cancer were immunostained to detect myeloid clusters, STAT3 activity and occult metastasis. Anthracosis intensity, myeloid cluster infiltration associated with anthracosis and pSTAT3 level were scored and correlated with patient survival. Multivariate Cox regression analysis was performed with prognostic variables. Human macrophages were used for in vitro nicotine treatment.
  
  
  RESULTS
  CD68+ myeloid clusters associated with anthracosis and with an immunosuppressive and metastasis-promoting phenotype and elevated overall STAT3 activity were observed in uninvolved lymph nodes. In patients with a smoking history, myeloid cluster score significantly correlated with anthracosis intensity and pSTAT3 level (P<0.01). Nicotine activated STAT3 in macrophages in long-term culture. CD68+ myeloid clusters correlated and colocalized with occult metastasis. Myeloid cluster score was an independent prognostic factor (P = 0.049) and was associated with survival by Kaplan-Maier estimate in patients with a history of smoking (P = 0.055). The combination of myeloid cluster score with either lymph node stage or pSTAT3 level defined two populations with a significant difference in survival (P = 0.024 and P = 0.004, respectively).
  
  
  CONCLUSIONS
  Myeloid clusters facilitate a pro-metastatic microenvironment in uninvolved regional lymph nodes and associate with occult metastasis in early stage non-small cell lung cancer. Myeloid cluster score is an independent prognostic factor for survival in patients with a history of smoking, and may present a novel method to inform therapy choices in the adjuvant setting. Further validation studies are warranted.
authors.affiliation: Department of Cancer Immunotherapy and Immunology, City of Hope Comprehensive Cancer Center, Duarte, California, United States of America.
authors.forename: Wang
authors.initials: W
authors.lastname: Zhang
authors.forename: Sumanta K
authors.initials: SK
authors.lastname: Pal
authors.forename: Xueli
authors.initials: X
authors.lastname: Liu
authors.forename: Chunmei
authors.initials: C
authors.lastname: Yang
authors.forename: Sachin
authors.initials: S
authors.lastname: Allahabadi
authors.forename: Shaira
authors.initials: S
authors.lastname: Bhanji
authors.forename: Robert A
authors.initials: RA
authors.lastname: Figlin
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
authors.forename: Karen L
authors.initials: KL
authors.lastname: Reckamp
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D055008:Anthracosis / Q000473:pathology; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology*; D008207:Lymphatic Metastasis; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D009538:Nicotine / Q000494:pharmacology; D010641:Phenotype; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D009538:Nicotine; D050796:STAT3 Transcription Factor; C067980:CD68 antigen, human; D000097382:CD68 Molecule