| ObjectiveTo study the prognostic significance of tumor-associated FOXP3+regulatory T cells (Tregs) and CD8+cytotoxic T lymphocytes (CTLs) in invasive breast carcinomas; To assess the affection of neoadjuvant chemotherapy on FOXP3+immunosuppressive T-cell infiltration in tumor microenvironment, and further clarify the association between tumor local immunity after chemotherapy and tumor response to chemotherapy and breast cancer prognosis. MethodsTregs and CTLs were assessed by immunohistochemistry in 1270 cases of invasive breast carcinoma did not receive any anti-cancer therapy before surgery for their associations with patient survival, histopathologic features and molecular subtypes. Surgical specimens from 132 patients with invasive breast cancer who received neoadjuvant chemotherapy were assessed by comparing with the diagnostic pre-treatment core biopsy and the pathological response to chemotherapy was graded by Miller-Payne grading system. Foxp3+ cell infiltrates before and after chemotherapy in different locations were detected by immunohistochemical method to analyze its sensitivity to chemotherapy and the association with chemotherapy response and breast cancer prognosis. Results1. Infiltrates of Tregs and CTLs were observed within tumor bed and in the tissue surrounding tumor. The lymphocytes infiltrating within tumors presented in a diffuse pattern and those in tissue surrounding tumors were more abundant and intended to form lymphoid aggregates.2. Within tumor bed, increased infiltration of Tregs and CTLs was significantly more common in those with unfavorable histologic features, including high histologic grade, and negative ER and PR status. In addition, high density Treg infiltration was also associated with tumor HER2 over-expression, decreased overall survival (OS) and progression-free survival (PFS).3. In tissue surrounding tumor, in contrast, high CTL/Treg ratio was found to be significantly associated with improved OS and PFS.4. These prognostic associations shown above were confirmed by multivariate analysis.5. Furthermore, the density of Treg infiltrates within tumors was inversely correlated with the prognosis of the molecular subtypes of tumors. The ratio of CTL/Treg infiltrates in the surrounding tissue was also significantly higher in luminal than non-luminal subtypes of carcinoma.6. In 132 cases of invasive breast cancer patients received neoadjuvant chemotherapy, the peritumoral infiltrating FOXP3+Tregs are more sensitive to chemotherapy than that in intratumoral infiltrates; Peritumoral infiltrating Tregs in different molecular subtypes of breast cancer showed different sensitivities to chemotherapy, among which the Treg densities in HER2-enriched and basal-like subtypes decreased significantly.7. Peritumoral rather than intratumoral FOXP3+Treg infiltration after chemotherapy is independent predictors of pathologic complete response (pCR), but intratumoral rather than peritumoral Treg infiltration is the independent predictor of OS and PFS by multivariate analysis. And intratumorai Treg infiltration showed higher relative risk and prognostic predictive value than the pathological response to chemotherapy by multivariate analysis.ConclusionsThe prognostic significances of Tregs and CTLs in breast carcinoma depend on their relative density and location. The density of intratumoral Treg infiltrates and the peritumoral CTL/Treg ratio are independent prognostic factors and correlated with the prognosis of the molecular subtypes of breast carcinoma, which may serve as potential target for stratifying immunotherapy to battle against the aggressive subtypes of breast carcinoma. The peritumoral infiltrating FOXP3+Treg is more sensitive to chemotherapy than that in intratumoral infiltrates and is independent predictors of pCR. However, intratumoral rather than peritumoral Treg infiltration is the independent predictor of OS and PFS both before and after chemotherapy. Thus, the Immunomodulatory/immune therapy or chemotherapy, or some combination of these therapeutic methods which could decrease intratumoral infiltrating FOXP3+ Tregs may play a more prominent role in improving the prognosis of breast cancer. |
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