title: Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells.
abstract: OBJECTIVE
  T-cell infiltration is associated with good tumor prognosis in many cancers. To assess the capacity of neoadjuvant chemotherapy to affect T-cell infiltration in breast cancer, we evaluated CD3 and CD8 infiltrates, and the Foxp3 immunosuppressive T cells.
  
  
  METHODS
  CD3+, CD8+, and Foxp3+ cell infiltrates were detected by immunohistochemistry in a series of 56 breast cancer patients before and after the end of neoadjuvant chemotherapy.
  
  
  RESULTS
  Poor prognostic factors (negative hormonal receptors, high tumor grade, and nodal involvement) were associated with a significantly higher number of CD3, CD8, and Foxp3 infiltrates before the beginning of chemotherapy. Chemotherapy resulted in a decrease in Foxp3 infiltrates, whereas the level of CD8 and CD3 infiltrates remained unchanged. Pathologic complete responses (pCR) had a drastic decrease of Foxp3+ cells, whereas these cells remained elevated in nonresponders. A cutoff criterion that combined high CD8 infiltration and no Foxp3 cell infiltration on surgical specimens is associated with pCR with a sensitivity of 75% and a specificity of 93%. The infiltrate of cytotoxic TiA1 and granzyme B-positive cells was dramatically enhanced after chemotherapy only in patients with pCR. By multivariate analysis, association of a high CD8 infiltration and no Foxp3 infiltration on final histologic specimens were independently associated with pCR.
  
  
  CONCLUSIONS
  These findings indicate that pCR to neoadjuvant chemotherapy is associated with an immunologic profile combining the absence of immunosuppressive Foxp3 cells and the presence of a high number of CD8 T cells and cytotoxic cells. These results argue for the induction of an antitumor immune response by chemotherapy.
authors.affiliation: Centre Régional de Lutte Contre le Cancer, Dijon, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ladoire
authors.forename: Laurent
authors.initials: L
authors.lastname: Arnould
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.forename: Bruno
authors.initials: B
authors.lastname: Coudert
authors.forename: Francois
authors.initials: F
authors.lastname: Martin
authors.forename: Bruno
authors.initials: B
authors.lastname: Chauffert
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D017252:CD3 Complex / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D017024:Chemotherapy, Adjuvant; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000502:physiology*; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D017252:CD3 Complex; D016827:CD8 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors