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Pathologic Complete Response to Neoadjuvant Chemotherapy of Breast Carcinoma Is Associated with the Disappearance of Tumor-Infiltrating Foxp3⁺ Regulatory T Cells

Authors' Affiliations: ¹ Centre Régional de Lutte Contre le Cancer and ² Institut National de la Sante et de la Recherche Medicale CRI-866, Faculty of Medicine, Dijon, France; and ³ Institut Gustave Roussy, Villejuif, France

Requests for reprints: François Ghiringhelli, Centre Georges Francois Leclerc, Centre de Recherche INSERM 866, Faculté de Médecine, 7 boulevard Jeanne D'Arc, 21000 Dijon, France. Phone: 33-3-80-39-33-53; Fax: 33-3-80-39-34-34; E-mail: francois.ghiringhelli{at}wanadoo.fr.

Purpose: 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.

Experimental Design: 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.

Conclusion: 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.