HDAC inhibition potentiates immunotherapy in triple negative breast cancer.

Triple-negative breast cancer (TNBC) represents a more aggressive and difficult subtype of breast cancer where responses to chemotherapy occur, but toxicity is significant and resistance often follows. Immunotherapy has shown promising results in various types of cancer, including breast cancer. Here, we investigated a new combination strategy where histone deacetylase inhibitors (HDACi) are applied with immune checkpoint inhibitors to improve immunotherapy responses in TNBC. Testing different epigenetic modifiers, we focused on the mechanisms underlying HDACi as priming modulators of immunotherapy. Tumor cells were co-cultured with human peripheral blood mononuclear cells (PBMCs) and flow cytometric immunophenotyping was performed to define the role of epigenetic priming in promoting tumor antigen presentation and immune cell activation. We found that HDACi up-regulate PD-L1 mRNA and protein expression in a time-dependent manner in TNBC cells, but not in hormone responsive cells. Focusing on TNBC, HDACi up-regulated PD-L1 and HLA-DR on tumor cells when co-cultured with PBMCs and down-regulated CD4+ Foxp3+ Treg in vitro. HDACi significantly enhanced the in vivo response to PD-1/CTLA-4 blockade in the triple-negative 4T1 breast cancer mouse model, the only currently available experimental system with functional resemblance to human TNBC. This resulted in a significant decrease in tumor growth and increased survival, associated with increased T cell tumor infiltration and a reduction in CD4+ Foxp3+ T cells in the tumor microenvironment. Overall, our results suggest a novel role for HDAC inhibition in combination with immune checkpoint inhibitors and identify a promising therapeutic strategy, supporting its further clinical evaluation for TNBC treatment

Autologous Fat Grafting as a Novel Antiestrogen Vehicle for the Treatment of Breast Cancer.

BackgroundAdipose fat transfer is increasingly used for contour corrections of the tumor bed after lumpectomy and breast reconstructions after mastectomy. The lipophilic nature of the fat tissue may render adipocytes an ideal vehicle with which to deliver a high boost of an antiestrogen to the tumor bed to serve as an adjunct systemic hormonal therapy. The authors therefore tested whether adipocytes could safely be loaded with an antiestrogen and allow for release at therapeutic concentrations to treat breast cancer.MethodsAdipose tissue was collected from patients undergoing autologous fat grafting. The influence of adipose tissue on tumorigenesis was determined both in vitro and in vivo using breast cancer cell lines. Ex vivo, adipose tissue was assessed for its ability to depot fulvestrant and inhibit the growth of breast cancer cell lines.ResultsAdipose tissue harvested from patients did not promote breast cancer cell growth in vitro or in an in vivo mouse model. Adipose tissue was successfully loaded with fulvestrant and released at levels sufficient to inhibit estrogen receptor signaling and growth of breast cancer cells.ConclusionsThis work supports the hypothesis that adipose tissue used for autologous fat grafting can serve as a novel method for local drug delivery. As this technique is used to reconstruct a variety of postsurgical defects following cancer resection, this approach for local drug delivery may be an effective alternative in therapeutic settings beyond breast cancer

Local delivery of hormonal therapy with silastic tubing for prevention and treatment of breast cancer.

Broad use of germline testing has identified an increasing number of women at risk for breast cancer with a need for effective chemoprevention. We report a novel method to selectively deliver various anti-estrogens at high drug levels to the breast tissue by implanting a device comprised of silastic tubing. Optimized tubing properties allow elution of otherwise poorly bioavailable anti-estrogens, such as fulvestrant, into mammary tissue in vitro and in vivo with levels sufficient to inhibit estrogen receptor activation and tumor cell proliferation. Implantable silastic tubing delivers fulvestrant selectively to mouse mammary fat tissue for one year with anti-tumor effects similar to those achieved with systemic fulvestrant exposure. Furthermore, local delivery of fulvestrant significantly decreases cell proliferation, as assessed by Ki67 expression, most effectively in tumor sections adjacent to tubing. This approach may thereby introduce a potential paradigm shift and offer a promising alternative to systemic therapy for prevention and early interception of breast cancer