Cutting Edge: Mast Cells Critically Augment Myeloid-Derived Suppressor Cell Activity

Abstract

Myeloid-derived suppressor cells (MDSCs) are primarily recognized for their immunosuppressive properties in malignant disease. However, their interaction with other innate immune cells and their regulation of immune responses, such as in parasitic infection, necessitate further characterization. We used our previously published mouse model of MDSC accumulation to examine the immunoregulatory role of MDSCs in B16 melanoma metastasis and Nippostrongylus brasiliensis infection. In this study, we demonstrate that the activity of MDSCs is dependent on the immune stimuli and subset induced. Monocytic MDSCs predictably suppressed antitumor immune responses but granulocytic MDSCs surprisingly enhanced the clearance of N. brasiliensis infection. Intriguingly, both results were dependent on MDSC interaction with mast cells (MCs), as demonstrated by adoptive-transfer studies in MC-deficient (KitWsh/Wsh) mice. These findings were further supported by ex vivo cocultures of MCs and MDSCs, indicating a synergistic increase in cytokine production. Thus, MCs can enhance both immunosuppressive and immunosupportive functions of MDSCs.

Mast Cells Boost Myeloid-Derived Suppressor Cell Activity and Contribute to the Development of Tumor-Favoring Microenvironment

“…The finding of a synergism between mast cells and MDSCs in the context of TNFa production led us to investigate whether a generalized increase in cytokine production is the outcome of this cellular interaction. Similar to results shown by Saleem and colleagues (15) and Morales and colleagues (16), whereas resting mast cells, either alone or together with M-MDSCs, released low or undetectable levels of the investigated mediators, coculture of activated mast cells and M-MDSCs resulted in a significant increase of IL6 and CCL-2 levels (Fig. 6A), similar to that observed for TNFa production.…”

“…Other findings by Cheon and colleagues (14) suggest that in the APCD468 murine model of colon polyposis, mast cells could support and mobilize MDSCs via 5-lipoxygenase activity to drive immune escape with an increase in polyp development. The idea that mast cells can enhance the immunosuppressive function of MDSCs is further supported by recent in vivo data showing that MDSCs depend on mast cells to exert their protumor suppressive function (15,16). Herein, we demonstrate the relevance of the interplay between mast cells and monocytic MDSCs in a colon cancer model and describe the molecular mechanisms involved.…”

Mast cell/MDSC a liaison immunosuppressive for tumor microenvironment

“…Of note, some aspects of the described bidirectional axis, such as MC promotion of MDSC trafficking and activity or MDSC enhancement of MC responses, are conserved also in other pathological settings such as parasitic infection 6 and airway hyper-responsiveness. 9 The bidirectional modulation resulting from this interaction highlights the mutual dependence of the two populations to exercise their maximum potential, with a positive (parasite clearance) or negative (cancer, airway hyperresponsiveness) outcome for the host, dependent on the context.…”

“…These data suggest that MCs are required to enhance MDSC-mediated immune suppression and tumor escape from immune response, with, in particular, a role attributed to the monocytic-MDSC subset. 6 We recently showed cell-to-cell interactions between MDSCs and MCs in the mucosa of colon carcinoma patients and in the colon and spleen of AOM/DSStreated mice. 7 The fact that, in the spleen, MCs can interact with and further amplify the potential of MDSCs to inhibit T cell proliferation could be viewed as a novel mechanism to amplify MDSC-dependent immune tolerance to tumor antigens in the spleen.…”

“…7 MDSC ability to selectively increase the production of cytokine (TNF-a, IL-6, IL-13) or chemokine (CCL2, CCL3) by IgE/Ag activated MCs (without a direct production by MDSCs), when co-cultured, is likewise reported and suggested to have an active modulatory effect on MC function. 6,9 Not surprisingly, all these mediators could be important pro-inflammatory and pro-tumoral agents as they are linked with MDSC activation and mobilization. Overall, our research further lends support to the role of MCs as bona fide recruiters and activators of MDSCs in a tumor microenvironment and proposes this axis as a potential therapeutical target.…”