Myeloid derived suppressor cells and the release of micro-metastases from dormancy

Metastasis is the primary cause of cancer mortality and an improved understanding of its pathology is critical to the development of novel therapeutic approaches. Mechanism-based therapeutic strategies require insight into the timing of tumor cell dissemination, seeding of distant organs, formation of occult lesions and critically, their release from dormancy. Due to imaging limitations, primary tumors can only be detected when they reach a relatively large size (e.g. > 1 cm 3 ), which, based on our understanding of tumor evolution, occurs approximately 10 years and about 30 doubling times following tumor initiation. Genomic profiling of paired primary tumors and metastases has suggested that tumor seeding at secondary sites occurs early during tumor progression and frequently, years prior to clinical diagnosis. Following seeding, tumor cells may enter into and remain in a dormant state, and if they survive and are released from dormancy, they can proliferate into an overt lesion. The timeline of tumor initiation and metastatic dormancy is regulated by tumor interactions with its microenvironment, angiogenesis, and tumor-specific cytotoxic T-lymphocyte (CTL) responses. Therefore, a better understanding of the cellular interactions responsible for immune evasion and/or tumor cell release from dormancy would facilitate the development of therapeutics targeted against this critical part of tumor progression. The immunosuppressive mechanisms mediated by myeloid-derived suppressor cells (MDSCs) contribute to tumor progression and, we posit, promote tumor cell escape from CTL-associated dormancy. Thus, while clinical and translational research has demonstrated a role for MDSCs in facilitating tumor progression and metastasis through tumor escape from adoptive and innate immune responses (T-, natural killer and B-cell responses), few studies have considered the role of MDSCs in tumor release from dormancy. In this review, we discuss MDSC expansion, driven by tumor burden associated growth factor secretion and their role in tumor cell escape from dormancy, resulting in manifest metastases. Thus, the therapeutic strategies to inhibit MDSC expansion and function may provide an approach to delay metastatic relapse and prolong the survival of patients with advanced malignancies.