The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects
Hidekazu Itamura, Takero Shindo, Isao Tawara, Yasushi Kubota, Ryusho Kariya, Seiji Okada, Krishna V. Komanduri, Shinya Kimura
Hidekazu Itamura, Takero Shindo, Isao Tawara, Yasushi Kubota, Ryusho Kariya, Seiji Okada, Krishna V. Komanduri, Shinya Kimura
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Research Article Hematology Transplantation

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects

Abstract

The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro. Here, we show that trametinib, a MEK inhibitor clinically approved for melanoma, suppresses GVHD safely without affecting GVT effects in vivo. Trametinib prolonged survival of GVHD mice and attenuated GVHD symptoms and pathology in the gut and skin. It inhibited ERK1/2 phosphorylation and expansion of donor T cells, sparing Tregs and B cells. Although high-dose trametinib inhibited myeloid cell engraftment, low-dose trametinib suppressed GVHD without severe adverse events. Notably, trametinib facilitated the survival of mice transplanted with allogeneic T cells and P815 tumor cells with no residual P815 cells observed in the livers and spleens, whereas tacrolimus resulted in P815 expansion. These results confirm that trametinib selectively suppresses GVHD-inducing T cells while sparing antitumor T cells in vivo, which makes it a promising candidate for translational studies aimed at preventing or treating GVHD.

Authors

Hidekazu Itamura, Takero Shindo, Isao Tawara, Yasushi Kubota, Ryusho Kariya, Seiji Okada, Krishna V. Komanduri, Shinya Kimura

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Figure 5

Trametinib spared graft-versus-tumor effects.

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Trametinib spared graft-versus-tumor effects. Irradiated B6D2F1 recipien...
Irradiated B6D2F1 recipients were infused with C57BL/6 TCD-BM with or without T cells, with or without P815 tumor cells. Vehicle or trametinib at 0.1 mg/kg was administered from day 0 through day 30. Combined data of 2 independent experiments (group a: n = 10, groups b–f: n = 18) are shown for survival (A) and percentage body weight (BW) (B). Statistical analyses were performed with the log-rank test (A) and the 2-tailed Student’s t test at day 42 (B), and no significant differences were detected. (C) H&E (left) and GFP (right) staining of the livers on day 9. Representative images of 3 analyses are shown. Original magnification, ×100. (D) P815 cells in the spleens on day 10 were detected as GFP+ cells by flow cytometry. Data are expressed as the percentages from 2 independent experiments, along with the mean value. (E and F) The spleens were harvested from 3 mice per group on day 33 (E), and cell numbers are expressed as the mean ± SEM (2-tailed Student’s t test with Bonferroni correction) (F). (G and H) T cells (G) or NK cells (H) from C57BL/6 (allogeneic; solid lines: n = 6) or DBA/2 (syngeneic; dashed lines: n = 3) mice were cocultured with P815 cells at different ratios. DMSO or trametinib at various concentrations was added to the media, and the percentage lysis of P815 cells was calculated by detecting PI-positive cells among CFSE-labeled cells. *P < 0.05.