Immunomodulation of FOXP3+ Regulatory T Cells by the Aromatase Inhibitor Letrozole in Breast Cancer Patients

Abstract

Purpose: We have shown previously that tumor infiltration by FOXP3 + regulatoryTcells (Treg) is associated with increased relapse and shorter survival of patients with both in situ and invasive breast cancer. Because estrogen regulatesTreg numbers in mice and promotes the proliferation of humanTregs, we hypothesized that blocking estrogen receptor-a signaling would abrogateTregs and be associated with response to hormonal therapy and increased survival. Experimental Design: FOXP3 + Tregs were quantified in tumor samples collected at baseline by incisional biopsy and after 6 months at definitive surgery in 83 elderly breast cancer patients (T 2-4 N 0-1 ) enrolled in a randomized phase II trial based on 6 months of primary letrozole (2.5 mg/d) or 6 months of letrozole plus oral ''metronomic''cyclophosphamide (50 mg/d). Results: Treg number ranged from 0 to 380 (median, 30) before treatment and from 0 to 300 (median, 8) after treatment. There was a significant reduction in Tregs in letrozole and letrozolecyclophosphamide patients (P < 0.0001and P < 0.002, respectively) after treatment.Treg number at residual histology was inversely related with response (P < 0.03 and P = 0.50, respectively) and a greaterTreg reduction was observed in responding patients (P < 0.03).Conclusion:This study suggests that aromatase inhibitors may have an indirect antitumor mechanism of action through reducingTregs in breast tumors and may be of use in estrogen receptora-negative tumors in combination with immunotherapy approaches.

A virosomal formulated Her-2/neu multi-peptide vaccine induces Her-2/neu-specific immune responses in patients with metastatic breast cancer: a phase I study

“…In tumor patients this suppressive effect on Tregs might be particularly crucial for the efficacy of a vaccine. Similar results have very recently been described in breast cancer patients treated with trastuzumab [30] as well as with an aromatase inhibitor [35], thus suggesting that overcoming Treg cell reconstitution might not only be seen in the present context, but perhaps also as an important contributor to success in a wider range of anti-tumor treatment strategies.…”

“…Recently, it was shown that tumor infiltration by Tregs is associated with a reduced survival of breast cancer patients [35]. Treg cells may also be responsible for the failure of an anticancer immune response by hindering the generation and activity of antitumor reactive T cells thereby maintaining self-tolerance to the tumor antigens.…”

Effect of Aromatase Inhibition on Functional Gene Modules in Estrogen Receptor–Positive Breast Cancer and Their Relationship with Antiproliferative Response

“…Hence, one explanation for this result could be that chemotherapy destroys not only the tumor, but also immune-associated cells, whereas endocrine therapy impacts more on cross-talk between the tumor and the immune system. This hypothesis is supported to some extent by recent data, which suggest that letrozole can decrease recruitment of regulatory T cells, which are known to dampen the immune response (44). Despite these distinct correlations between the E2F3 signature and other modules, no correlation was found between E2F3 and Ki67 protein expression at the baseline, in the presence or absence of the PAGs.…”

Evaluation of Inflammatory Cells (Tumor Infiltrating Lymphocytes) in Solid Tumors

“…Toho by se dalo terapeuticky využít, protože je známo, že jak hormonální terapie, tak i cytotoxická terapie má imunomodulační účinky a ně kte ré léky, např. inhibitory aromatázy mohou působit proti imunosupresivnímu efektu estrogenů kupříkladu redukcí počtu Treg [60].…”