Apoptosis Regulation and Immune Suppressive Programs in Tumor-Conditioned Monocytes
Immunology Section, Department of Medicine, Verona University Hospital, Italy
Myeloid-derived suppressor cells (MDSCs) are characterized by their myeloid origin, heterogeneous cell composition and ability to regulate negatively adaptive and innate immune responses to cancer. In addition, their presence and frequency in the blood of cancer patients is emerging as a potential prognostic marker to monitor clinical outcome and response to therapy. Among different subsets, monocytic (M)-MDSC are extremely susceptible to low dose chemotherapy, to the point that administration of different agents can increase the efficacy of adoptive cell therapy with tumor antigen-specific CD8+ T cells by eliminating in vivo the immune suppressive M-MDSCs. Although endowed with different mechanisms of cell damage, the chemotherapeutic agents effective on M-MDSCs share the ability to down-regulate the expression of the same anti-apoptotic molecule. Surprisingly, not only M-MDSCs are poisoned and need to express this protein for their survival but the very same molecule regulates a complex transcriptional program. Human monocytes infected with lentiviruses vectorsexpressing this apoptotic regulator modulated more than 750 genes including IDO1, CD274, CD273, IL-10, and CD124. Moreover, this enforced expression generated strongly suppressive MDSCs, able to inhibit both in vitro and in vivo T cell activation and proliferation, mitigate the severity of graft versus host disease in xenogenic mouse models. The connection between apoptosis regulation and immune modulation was further exploited in transgenic mice that constitutively express an active form of the gene in the myeloid cell lineage. This novel, unexpected link between apoptosis and immune regulation in monocytes can have potential applications for the development of immune regulatory and cell-based therapeutic strategies, as well as representing a biomarker for cancer patients.