title: Tumor-infiltrating immune cell profiles and their change after neoadjuvant chemotherapy predict response and prognosis of breast cancer.
abstract: BACKGROUND
  Tumor microenvironment immunity is associated with breast cancer outcome. A high lymphocytic infiltration has been associated with response to neoadjuvant chemotherapy, but the contribution to response and prognosis of immune cell subpopulations profiles in both pre-treated and post-treatment residual tumor is still unclear.
  
  
  METHODS
  We analyzed pre- and post-treatment tumor-infiltrating immune cells (CD3, CD4, CD8, CD20, CD68, Foxp3) by immunohistochemistry in a series of 121 breast cancer patients homogeneously treated with neoadjuvant chemotherapy. Immune cell profiles were analyzed and correlated with response and survival.
  
  
  RESULTS
  We identified three tumor-infiltrating immune cell profiles, which were able to predict pathological complete response (pCR) to neoadjuvant chemotherapy (cluster B: 58%, versus clusters A and C: 7%). A higher infiltration by CD4 lymphocytes was the main factor explaining the occurrence of pCR, and this association was validated in six public genomic datasets. A higher chemotherapy effect on lymphocytic infiltration, including an inversion of CD4/CD8 ratio, was associated with pCR and with better prognosis. Analysis of the immune infiltrate in post-chemotherapy residual tumor identified a profile (cluster Y), mainly characterized by high CD3 and CD68 infiltration, with a worse disease free survival.
  
  
  CONCLUSIONS
  Breast cancer immune cell subpopulation profiles, determined by immunohistochemistry-based computerized analysis, identify groups of patients characterized by high response (in the pre-treatment setting) and poor prognosis (in the post-treatment setting). Further understanding of the mechanisms underlying the distribution of immune cells and their changes after chemotherapy may contribute to the development of new immune-targeted therapies for breast cancer.
authors.affiliation: Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain. helenagarciam@gmail.com.
authors.forename: Elena
authors.initials: E
authors.lastname: García-Martínez
authors.affiliation: Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain. gines.luengo@um.es.
authors.forename: Ginés Luengo
authors.initials: GL
authors.lastname: Gil
authors.affiliation: Department of Pathology, University Hospital Morales Meseguer, Murcia, Spain. mariaa.chaves@carm.es.
authors.forename: Asunción Chaves
authors.initials: AC
authors.lastname: Benito
authors.affiliation: Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain. engonbil@um.es.
authors.forename: Enrique
authors.initials: E
authors.lastname: González-Billalabeitia
authors.affiliation: Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain. marianvico@yahoo.es.
authors.forename: María Angeles Vicente
authors.initials: MA
authors.lastname: Conesa
authors.affiliation: Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain. tggarc@gmail.com.
authors.forename: Teresa
authors.initials: T
authors.lastname: García García
authors.affiliation: Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain. eliggarre3@gmail.com.
authors.forename: Elisa
authors.initials: E
authors.lastname: García-Garre
authors.affiliation: Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain. vvg@um.es.|Centro Regional de Hemodonación, Murcia, Spain. vvg@um.es.
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
authors.affiliation: Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia, Spain. frayala@um.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ayala de la Peña
mesh_terms: D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D018951:Antigens, CD20 / Q000276:immunology / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011379:Prognosis; D043823:Taxoids / Q000627:therapeutic use; D000068878:Trastuzumab; D059016:Tumor Microenvironment / Q000276:immunology*; D055815:Young Adult; D000097382:CD68 Molecule
chemical_list: D018943:Anthracyclines; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D018951:Antigens, CD20; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D051858:Forkhead Transcription Factors; D043823:Taxoids; D000068878:Trastuzumab; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C418974:FOXP3 protein, human