title: Intratumoral regulatory T cells as an independent predictive factor for pathological complete response to neoadjuvant paclitaxel followed by 5-FU/epirubicin/cyclophosphamide in breast cancer patients.
abstract: Anti-tumor immunity is thought to play a significant role in chemotherapeutic response of breast tumors. In the present study, we investigated whether tumor infiltrating FOXP3+ regulatory T cells, CD8+ cytotoxic T cells, and IL17F+ helper T cells were associated with a pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). Breast cancer patients (stages II and III, n = 180) who were treated with NAC consisting of sequential weekly paclitaxel followed by 5-FU/epirubicin/cyclophosphamide were included for this study. Core needle tumor specimens obtained before NAC were immunohistochemically examined for FOXP3, CD8, and IL17F. Intratumoral infiltration of FOXP3+, CD8+, and IL17F+ T cells was observed in 62.2, 80.0, and 62.2 % of tumors, respectively. FOXP3 and CD8 infiltrates, but not IL17F infiltrate, were significantly (P < 0.001 and P = 0.007, respectively) associated with a high-pCR rate (31.3 and 25.7 %, respectively), and breast tumors with both FOXP3 and CD8 infiltrates showed the highest pCR rate (33.0 %). Multivariate analysis indicated that only FOXP3 infiltrates (P = 0.014) and the conventional predictive factor Ki67 (P = 0.031) were statistically significant and independent predictors of pCR. Breast tumors with FOXP3 and CD8 infiltrates were more likely to achieve pCR. FOXP3 infiltrate, in combination with Ki67, could thus be used as a clinically useful predictor of response to NAC. The possible indirect mechanism through which chemotherapy exerts its anti-tumor activity, i.e., enhancing anti-tumor immunity by inhibiting FOXP3, was also suggested.
authors.affiliation: Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Oda
authors.forename: Kenzo
authors.initials: K
authors.lastname: Shimazu
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Naoi
authors.forename: Koji
authors.initials: K
authors.lastname: Morimoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shimomura
authors.forename: Masashi
authors.initials: M
authors.lastname: Shimoda
authors.forename: Naofumi
authors.initials: N
authors.lastname: Kagara
authors.forename: Naomi
authors.initials: N
authors.lastname: Maruyama
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Shinzaburo
authors.initials: S
authors.lastname: Noguchi
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*
chemical_list: D054316:Biomarkers, Pharmacological; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C440021:IL17F protein, human; D020381:Interleukin-17; D015251:Epirubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D005472:Fluorouracil