Williams Cancer Institute




In recent decades, immune checkpoint blockade therapy has shown great promise in treating multiple types of cancer by strengthening the body’s immune response. However, many patients do not respond well to this therapy, possibly due to the presence of immunosuppressive cells in the tumor microenvironment. Myeloid-derived suppressor cells (MDSCs) have been found to play a significant role in suppressing anti-tumor immunity and may cause resistance to immune checkpoint blockade therapy. The effects of valproic acid (VPA), a safe drug used to treat epilepsy, on MDSCs are being investigated with the aim of enhancing the efficacy of immune checkpoint blockade therapy.

In a study conducted by Xie et al in 2020 at Osaka University, EL4 and B16-F10 cell lines were used, which were maintained in specific media according to the American Type Culture Collection (ATCC) instructions. C57BL/6J mice were used in murine tumor studies, where EL4 or B16-F10 cells were subcutaneously injected into mice to induce tumor growth. Treatments with valproic acid (VPA) and specific antibodies were administered at different times to evaluate their effect on tumor progression and the immune response.
For cellular studies, cells were isolated from bone marrow, spleen, and tumors of mice. These cells were used for flow cytometry analysis, MDSC suppression assays, and proliferation assays of T cells and natural killer (NK) cells. In addition, in vitro chemotaxis assays were performed to study cell migration. Statistical analyses were performed using Student’s t-tests, one- or two-way analysis of variance (ANOVA), and a p-value of <0.05 was considered statistically significant.

The results show that valproic acid (VPA) delays the progression of EL4 and B16-F10 tumors and reactivates tumor-infiltrating immune cells. It was evaluated whether VPA alone had an anti-tumor effect in anti-PD-1-sensitive EL4 lymphoma and anti-PD-1-resistant B16-F10 melanoma mouse models. It has been previously reported about the induction of myeloid-derived suppressor cells (MDSCs) and their infiltration into tumors in both models. These processes play a key role in suppressing anti-tumor T-cell activity. VPA alone delayed tumor growth in EL4 lymphoma-bearing mice and prolonged survival. In the B16-F10 melanoma-bearing mouse model, mice that received VPA also showed slower tumor progression and longer survival than those that received PBS.

To determine if the inhibition of tumor growth caused by VPA was associated with an enhanced immune response, tumor-infiltrating lymphoid and myeloid populations in EL4 tumors were examined. A reduction in the level of MDSCs at the tumor site was observed, while there were no significant changes in the levels of tumor-associated macrophages (TAMs) and regulatory T cells (Tregs). Additionally, an increase in natural killer (NK) cells and CD8+ T cells in tumors and peripheral blood was found, along with an increase in the early activation marker CD69 in NK and CD8+ T cells.
It was demonstrated that the anti-tumor effect of VPA is dependent on anti-tumor immune cells. The anti-tumor effect of VPA was completely absent in mice whose NK cells were depleted in the EL4 tumor model, while depletion of CD8+ T cells alone had a lesser effect. Furthermore, it was investigated whether VPA directly affected the immunosuppressive activity of MDSCs. It was observed that VPA reduced the immunosuppressive activity of polymorphonuclear MDSCs (PMN-MDSCs) but had little effect on that of monocytic MDSCs (M-MDSCs).

Reference: Zhiqi Xie, Tamami Ikegami, Yukio Ago, Naoki Okada & Masashi Tachibana, 29 Feb 2020, Valproic acid attenuates CCR2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progression, https://www.tandfonline.com/doi/full/10.1080/2162402X.2020.1734268

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