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

Abstract

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 Tcells. 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 TiA1and 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.

Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target

“…Recent studies have also shown that successful chemotherapeutic treatments for breast carcinoma, which resulted in a complete pathologic response also resulted in the disappearance of FoxP3-positive T cells and an increased number of CD8 þ cytotoxic T cells. 31 We observed associations between elevated numbers of FoxP3-positive cells and the more aggressive tumor phenotypes of advanced Nottingham grade (grade III) and larger tumor size (42.0 cm). One of the most aggressive breast cancer phenotypes, the so-called 'triple negative' (ER, PR, and Her2/neu) Nottingham grade III cancer, was also significantly associated with higher average numbers of FoxP3-positive cells.…”

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

“…In line with these results, it has been shown that clinical response to chemotherapy is often associated with a reduction in TITregs and the recruitment of intratumoral CD8 + T cells [95]. Moreover, imatinib mesylate (a small agent initially developed as a BCR-ABL-specific inhibitor) has been demonstrated to potentiate antitumor T-cell responses in patients affected by gastrointestinal stromal tumors by inhibiting IDO expression (by tumor cells) and hence promoting the apoptotic demise of Tregs [96].…”

Development of a live and highly attenuated Listeria monocytogenes-based vaccine for the treatment of Her2/neu-overexpressing cancers in human

“…In breast cancer patients receiving neoadjuvant chemotherapy, a higher intratumoral CD8 þ /FoxP3 ratio has been correlated with a favorable response to the treatment, as compared with unchanged ratios in nonresponders. 17 Particularly, this treatment resulted in a decrease in FoxP3 þ , but no change in CD8 þ and CD3 þ T-cell infiltrates, with a significant increase in cytotoxic markers, such as TiA1 and granzyme B. 17 It is noteworthy that the LmddA vector expressing an irrelevant antigen (HPV16 E7) was also associated with a significant decrease in the frequency of Tregs in the tumors, likely as a consequence of innate immunity responses.…”

“…17 Particularly, this treatment resulted in a decrease in FoxP3 þ , but no change in CD8 þ and CD3 þ T-cell infiltrates, with a significant increase in cytotoxic markers, such as TiA1 and granzyme B. 17 It is noteworthy that the LmddA vector expressing an irrelevant antigen (HPV16 E7) was also associated with a significant decrease in the frequency of Tregs in the tumors, likely as a consequence of innate immunity responses. The ability of bacteria to silence Tregs has been already described.…”

“…17 To establish the mechanisms behind anti-tumor effects of ADXS31-164, the frequency of CD8 þ effector T cells in relation to Tregs in spleens and tumors of mice was determined. Splenocytes and intratumoral lymphocytes were isolated after three immunizations and stained for Tregs, which were defined as A Listeria vaccine for treatment of Her2 þ tumors V Shahabi et al mice in negative control group had already succumbed to their tumors, but all mice in ADXS31-164 group were still alive, with only small signs of tumor growth.…”