Abstract
Intratumoral infiltration of myeloid-derived suppressor cells (MDSCs) is known to promote neoplastic growth by inhibiting the tumoricidal activity of T cells. However, direct interactions between patient-derived MDSCs and circulating tumors cells (CTCs) within the microenvironment of blood remain unexplored. Dissecting interplays between CTCs and circulatory MDSCs by heterotypic CTC/MDSC clustering is critical as a key mechanism to promote CTC survival and sustain the metastatic process. We characterized CTCs and polymorphonuclear-MDSCs (PMN-MDSCs) isolated in parallel from peripheral blood of metastatic melanoma and breast cancer patients by multi-parametric flow cytometry. Transplantation of both cell populations in the systemic circulation of mice revealed significantly enhanced dissemination and metastasis in mice co-injected with CTCs and PMN-MDSCs compared to mice injected with CTCs or MDSCs alone. Notably, CTC/PMN-MDSC clusters were detected in vitro and in vivo either in patients’ blood or by longitudinal monitoring of blood from animals. This was coupled with in vitro co-culturing of cell populations, demonstrating that CTCs formed physical clusters with PMN-MDSCs; and induced their pro-tumorigenic differentiation through paracrine Nodal signaling, augmenting the production of reactive oxygen species (ROS) by PMN-MDSCs. These findings were validated by detecting significantly higher Nodal and ROS levels in blood of cancer patients in the presence of naïve, heterotypic CTC/PMN-MDSC clusters. Augmented PMN-MDSC ROS upregulated Notch1 receptor expression in CTCs through the ROS-NRF2-ARE axis, thus priming CTCs to respond to ligand-mediated (Jagged1) Notch activation. Jagged1-expressing PMN-MDSCs contributed to enhanced Notch activation in CTCs by engagement of Notch1 receptor. The reciprocity of CTC/PMN-MDSC bi-directional paracrine interactions and signaling was functionally validated in inhibitor-based analyses, demonstrating that combined Nodal and ROS inhibition abrogated CTC/PMN-MDSC interactions and led to a reduction of CTC survival and proliferation. This study provides seminal evidence showing that PMN-MDSCs, additive to their immuno-suppressive roles, directly interact with CTCs and promote their dissemination and metastatic potency. Targeting CTC/PMN-MDSC heterotypic clusters and associated crosstalks can therefore represent a novel therapeutic avenue for limiting hematogenous spread of metastatic disease.
Highlights
Transit through the circulatory system imposes a hostile environment on circulating tumor cells (CTCs), which are shed from primary and/or metastatic tumors and known “seeds” of fatal metastatic disease
We found that melanoma patients had 16.5% higher (* p = 0.02), while breast cancer patients had 49.1% higher (** p < 0.001) levels of exogenous reactive oxygen species (ROS) compared to healthy donors (Figure 5A).2.3
CTCs shed intermittently by primary and metastatic tumors represent the fundamental pre-requisites to originate either metastasis (CTC shed from primary tumors), or metastasis of metastasis (CTC shed from primary metastatic disease)
Summary
Transit through the circulatory system imposes a hostile environment on circulating tumor cells (CTCs), which are shed from primary and/or metastatic tumors and known “seeds” of fatal metastatic disease. Under the impact of tumor-cell derived signals, PMNs are at a phenotypically “immature” developmental stage and display inhibitory function in T cell activation [4]. These cells are designated PMN myeloid-derived suppressor cells (PMN-MDSCs). Many reports have demonstrated pro-tumorigenic roles of PMN-MDSCs at multiple levels and stages of metastasis, including the suppression of the adaptive immune response, effects on tumor angiogenesis and cancer stem cell properties, and shaping the generation of pre-metastatic niches (reviewed in [4,5,6,7]). Despite the important roles played by MDSCs altering tumor cell-initiating competence and providing pre-metastatic niches [7,8,9,10], mechanisms underlying direct effects of circulatory PMN-MDSCs on CTCs are not understood
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