Effect of lenalidomide on alloresponses of adult perpheral blood

Immunomodulatory drugs (IMiDs), such as lenalidomide provide a tool to enhance both direct anti-tumor and graft-versus-tumor effects after allogeneic haematopoietic stem-cell transplantation (AHCT). However, early clinical experience with IMiDs after AHCT using adult peripheral blood (APB) as a stem cell source has been limited by induction of graft-versus-host disease. Characterization of the mechanisms by which IMIDs can modulate alloresponses of T-cells from different cell sources could facilitate more effective use of these drugs in the setting of AHCT. In this study we have used in vitro modelling to identify changes in alloresponses of APB and umbilical cord blood (UCB) T-cells after exposure to the widely used IMiD lenalidomide. We demonstrate that lenalidomide increases net alloproliferation of APB T-cells by selectively enhancing allospecific proliferation of CD8+ T-cells. These CD8+ T-cells have enhanced effector memory differentiation, are enriched for polyfunctional effectors, and have a distinct gene expression profile with altered expression of key immunoregulatory genes. In contrast, although lenalidomide treatment of UCB T-cells results in a similar increase in alloreactive effector CD8+ T-cells, it also reduces allospecific proliferation of CD4+ T-cells and selectively expands frequencies of CD4+ regulatory T-cells, resulting in a net reduction in UCB T-cell alloproliferation. Our findings show that lenalidomide has a qualitatively different impact on alloresponses of T-cells from different cell sources, with a potentially tolerogenic effect on UCB T-cells. These findings have important implications for the future use of IMiDs in the setting of AHCT.

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