MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner

Abstract

Key Points• RAS/MEK/ERK signaling is memory stage-dependent in human T cells, conferring susceptibility to alloreactive T-cell selective inhibition.• MEK inhibitors selectively inhibit alloreactive but not herpesvirus-specific human T cells and inhibit murine GVHD.Immunosuppressive strategies currently used in hematopoietic stem cell transplantation reliably decrease graft-versus-host disease (GVHD) rates, but also impair pathogenspecific immunity. Experimental transplant studies indicate that GVHD-initiating alloreactive T cells reside primarily in naive and central memory T-cell compartments. In contrast, virus-specific T cells comprise a more differentiated memory population. After finding that the rat sarcoma/mitogen-activated protein kinase kinase/extracellular receptor kinase (RAS/MEK/ERK) pathway is preferentially activated in naive and central memory human T cells, we hypothesized that MEK inhibitors would preferentially inhibit alloreactive T cells, while sparing more differentiated virus-specific T cells. Confirming our hypothesis, we found that MEK inhibitors including selumetinib preferentially inhibited cytokine production and alloreactivity mediated by naive and central memory human CD4 1 and CD8 1 T cells while sparing more differentiated T cells specific for the human herpesviruses cytomegalovirus and Epstein-Barr virus. We then demonstrated that short-term posttransplant administration of selumetinib in a major histocompatibility complex major-and minor-mismatched murine model significantly delayed the onset of GVHD-associated mortality without compromising myeloid engraftment, demonstrating the in vivo potential of MEK inhibitors in the setting of hematopoietic stem cell transplantation. These findings demonstrate that targeting memory-dependent differences in T-cell signaling is a potent and selective approach to inhibition of alloreactivity. (Blood. 2013;121(23):4617-4626)

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

“…Though it is not clear whether the in vivo results derived from murine BMT models can be directly translated into human hematopoietic stem cell transplantation, our results are consistent with the in vitro results with human lymphocytes (17). As trametinib has already been approved for clinical use in the treatment of therapy-resistant melanoma and the safety of trametinib has been confirmed, we believe that our findings justify the use of trametinib to prevent and/or treat GVHD in clinical trials.…”

“…And it is interesting that trametinib reduced early deaths by day 10 after BMT, though clinical GVHD scores were still minimal (Figure 1, A and C). It is possible that MEK inhibition suppresses cytokine-releasing syndrome right after BMT, which is consistent with our previous results (17) and would be beneficial in the clinic.…”

“…MEK inhibitors affect human T cells in a memory stage-dependent manner, i.e., they selectively inhibit naive and central memory T cells while sparing effector memory T cells (17). In our murine GVHD models, most T cells had differentiated into effector memory T cells; however, some naive T cells were still detected in the spleens of trametinib-treated mice ( Figure 1D), implying that trametinib suppressed the functional differentiation of naive T cells into effector memory T cells.…”

“…In a mouse model of GVHD, this pathway was activated in T cells (16). We previously investigated the phosphorylation status of ERK1/2 during the activation of human T cells and found that the RAS/MEK/ERK pathway is preferentially activated in naive and central memory T cells but not in effector memory T cells (17). We then confirmed that MEK inhibitors selectively suppressed alloreactivity of T cells while sparing herpesvirus-specific T cells and showed that the MEK inhibitor selumetinib delayed the onset of murine GVHD (17).…”

Immuno-oncology Combinations: A Review of Clinical Experience and Future Prospects

“…BRAF inhibitors may also increase TILs and enhance antigen presentation (64,65). Interestingly, while the BRAF inhibitors have a potentiating effect on the immune system, MEK inhibitors have a possible reverse effect, reducing the secretion of cytokines (66) and reducing the activity of T lymphocytes (65) and DCs (67).…”