Myeloid-Derived Suppressor Cells Impair B Cell Responses in Lung Cancer through IL-7 and STAT5

Abstract

Myeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity, affecting amino acid metabolism and T cell function in the tumor microenvironment. However, it is unknown whether MDSCs regulate B cell responses during tumor progression. Using a syngeneic mouse model of lung cancer, we show reduction in percentages and absolute numbers of B cell subsets including pro-, pre-, and mature B cells in the bone marrow (BM) of tumor-bearing mice. The kinetics of this impaired B cell response correlated with the progressive infiltration of MDSCs. We identified that IL-7 and downstream STAT5 signaling that play a critical role in B cell development and differentiation were also impaired during tumor progression. Global impairment of B cell function was indicated by reduced serum IgG levels. Importantly, we show that anti-Gr-1 Ab-mediated depletion of MDSCs not only rescued serum IgG and IL-7 levels but also reduced TGF-β1, a known regulator of stromal IL-7, suggesting MDSC-mediated regulation of B cell responses. Furthermore, blockade of IL-7 resulted in reduced phosphorylation of downstream STAT5 and B cell differentiation in tumor-bearing mice and administration of TGF-β-blocking Ab rescued these IL-7-dependent B cell responses. Adoptive transfer of BM-derived MDSCs from tumor-bearing mice into congenic recipients resulted in significant reductions of B cell subsets in the BM and in circulation. MDSCs also suppressed B cell proliferation in vitro in an arginase-dependent manner that required cell-to-cell contact. Our results indicate that tumor-infiltrating MDSCs may suppress humoral immune responses and promote tumor escape from immune surveillance.

Myeloid-derived suppressor cells—new and exciting players in lung cancer

“…The criteria for characterizing the phenotype of MDSCs by flow cytometry are relatively defined, and immunosuppressive function is a functional standard defined for MDSCs. While MDSCs were initially described as merely T cell suppressive, emerging evidence suggests that MDSCs also interact with and modulate the function of other immune cells, particularly macrophages (Mø) [29,30], NK cells [31,32], Treg cells [33], and B cells [34]. Moreover, MDSCs, TAMs, and dendritic cells (DCs) have been reported to interact and cross-promote their immunosuppressive activities in the tumor microenvironment [35].…”

“…Most of the impairments were attributable to the direct effects of MDSCs, and they were related to and seemingly mediated by a IL-7-mediated reduction in STAT5 signaling and dysfunctional B cell responses. In addition, the authors revealed that TGF-β (an MDSC-associated cytokine) was a central inhibitor of IL-7 signaling in B cells in the TIME [34].…”

Myeloid‐derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

“…This mechanism could exist in obese prostate cancer patients . Besides STAT3, the other STAT family members including STAT1, STAT5 and STAT6 also have significant effects on the activity and function of MDSCs . After activation by IL‐1β and IFN‐γ, STAT1 suppresses the activity of T cells by promoting the secretion of iNOS and Arg‐1 of MDSCs, while STAT6 can regulate the suppressive effects of STAT1.…”

Myeloid derived suppressor cells in cancer, premalignancy and inflammation: A roadmap to cancer immunoprevention

“…MDSC have additionally been shown to inhibit natural killer cell Fc receptor mediated functions including antibody‐dependent cellular cytotoxicity (ADCC), cytokine production, and signal transduction 29 . MDSC also impair B cell differentiation and proliferation 30 …”

“…Use of a CCR2 antagonist recapitulated the genetic ablation results. Blocking CCL2 inhibited MDSC recruitment and delayed tumor progression in a lung cancer model, added along with a combination treatment with anti‐PD1 antibody, resulted in higher infiltration of T cells and production of interferon γ, which corresponded to an increase in survival 30,79 …”