Williams Cancer Institute



Breast cancer is one of the most common diseases among women, and its treatment poses a significant medical challenge. Radiotherapy has long been a cornerstone in the battle against this type of cancer, as it not only directly targets cancer cells but can also trigger an immune response against the tumor. However, despite its benefits, radiotherapy can, in some cases, promote immune evasion and contribute to cancer recurrence.

In this context, tumor-associated macrophages (TAMs) have emerged as key players in breast cancer dynamics. These cells, residing in the tumor microenvironment, can both promote and inhibit cancer growth, depending on their activation and polarization. On the other hand, the activation and recruitment of cytotoxic lymphocytes (CTLs), such as CD8+ T cells, have been shown to be crucial in cancer immunotherapy.

A promising area of research in this field is the use of histone deacetylase inhibitors (HDACis), such as valproic acid (VPA). These compounds have the potential to enhance the response to breast cancer treatment by modulating the immune system and altering the tumor microenvironment.

In a study conducted by Cai et al. in 2021, the effect of VPA and its analog, HPTA, in combination with radiotherapy in breast cancer models in rats was investigated. Using a primary breast cancer model induced in female Sprague-Dawley rats, the researchers observed a significant inhibition of tumor growth in rats treated with VPA/HPTA compared to those treated with radiotherapy alone. This effect was associated with a reduction in tumor cell proliferation and morphological changes indicative of cellular necrosis.

Furthermore, treatment with VPA/HPTA led to an increase in macrophage infiltration in the tumor microenvironment, with polarization towards the M1 phenotype, which is associated with anti-tumoral properties. An increase in bone marrow-derived macrophage population was also observed in tumors treated with VPA/HPTA, suggesting recruitment of immune cells to the tumor site.

One of the most significant findings was the activation of the anti-tumor immune response mediated by CD8+ cells after treatment with VPA/HPTA. This manifested in increased infiltration of CD8+ cells in the tumor microenvironment and higher expression of granzyme-B, a marker of cytotoxic activity of CD8+ cells.

In addition to these immunomodulatory effects, treatment with VPA/HPTA also resulted in a reduction in tumor vascularization, suggesting an anti-angiogenic effect.

In summary, the results of this study suggest that VPA and its analog, HPTA, may enhance the efficacy of radiotherapy in breast cancer treatment by activating the immune system and reprogramming the tumor microenvironment. However, further research is needed to better understand the underlying mechanisms and develop optimal clinical strategies for implementation.

Combining therapies targeting the immune system, such as VPA/HPTA, with immune checkpoint inhibitors could represent a promising strategy to further improve the efficacy of breast cancer treatment in the future.

Reference: Cai, Z., Lim, D., Liu, G., Chen, C., Jin, L., Duan, W., Ding, C., Sun, Q., Peng, J., Dong, C., Zhang, F., & Feng, Z., 11 May 2021, Valproic Acid-Like Compounds Enhance and Prolong the Radiotherapy Effect on Breast Cancer by Activating and Maintaining Anti-Tumor Immune Function. https://doi.org/10.3389/fimmu.2021.646384

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