Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells in cancer patients and tumor-bearing mice that potently inhibits T cell responses. During tumor progression, MDSCs accumulate in several organs, including the tumor tissue. So far, tumor-infiltrating MDSC subpopulations remain poorly explored. In this study, we performed global gene expression profiling of mouse tumor-infiltrating granulocytic and monocytic (MO-MDSC) subsets compared with MDSCs from peripheral blood. RMA-S lymphoma–infiltrating MO-MDSCs not only produced high levels of NO and arginase-1, but also greatly increased levels of chemokines comprising the CCR5 ligands CCL3, CCL4, and CCL5. MO-MDSCs isolated from B16 melanoma and from skin tumor–bearing ret transgenic mice also expressed high levels of CCL3, CCL4, and CCL5. Expression of CCR5 was preferentially detected on regulatory T cells (Tregs). Accordingly, tumor-infiltrating MO-MDSCs directly attracted high numbers of Tregs via CCR5 in vitro. Intratumoral injection of CCL4 or CCL5 increased tumor-infiltrating Tregs, and deficiency of CCR5 led to their profound decrease. Moreover, in CCR5-deficient mice, RMA-S and B16 tumor growth was delayed emphasizing the importance of CCR5 in the control of antitumor immune responses. Overall, our data demonstrate that chemokines secreted by tumor-infiltrating MO-MDSCs recruit high numbers of Tregs revealing a novel suppressive role of MDSCs with potential clinical implications for the development of cancer immunotherapies.
Natural killer (NK) cells are potent immune effector cells capable of mediating antitumor responses. Thus, during immunoediting, tumor cell populations evolve strategies to escape NK-cell-mediated recognition. In this study, we report a novel mechanism of immune escape involving tumor cell shedding of B7-H6, a ligand for the activating receptor NKp30 that mediates NK-cell binding and NK-cell-mediated killing. Tumor cells from different cancer entities released B7-H6 by ectodomain shedding mediated by the cell surface proteases "a disintegrin and metalloproteases" (ADAM)-10 and ADAM-17, as demonstrated through the use of pharmacologic inhibitors or siRNA-mediated gene attenuation. Inhibiting this proteolytic shedding process increased the levels of B7-H6 expressed on the surface of tumor cells, enhancing NKp30-mediated activation of NK cells. Notably, we documented elevated levels of soluble B7-H6 levels in blood sera obtained from a subset of patients with malignant melanoma, compared with healthy control individuals, along with evidence of elevated B7-H6 expression in melanoma specimens in situ. Taken together, our results illustrated a novel mechanism of immune escape in which tumor cells impede NK-mediated recognition by metalloprotease-mediated shedding of B7-H6. One implication of our findings is that therapeutic inhibition of specific metalloproteases may help support NK-cell-based cancer therapy. Cancer Res; 74(13); 3429-40. Ó2014 AACR.
IntroductionEffective antitumor immune responses require a close collaboration between armed effector cells of the innate and the adaptive immune system. The success of immune responses against tumors is often limited due to multiple regulatory mechanisms, including an immune suppressive tumor environment and an expansion of suppressive cell types. It is well established that regulatory T cells (Tregs) inhibit antitumor immune responses in vitro and in vivo. Furthermore, immature myeloid cells were described to accumulate in cancer patients and tumor-bearing mice and to suppress the proliferation and cytokine production of T cells (reviewed in Serafini et al 1 and Sica and Bronte 2 ). These cells were recently defined as myeloid-derived suppressor cells (MDSCs). 3 MDSCs are characterized by a combination of phenotypical and functional properties. With regards to their phenotype, mouse MDSCs represent a heterogeneous population of immature myeloid cells expressing CD11b and Gr-1. Additional markers, including F4/80, CD31, or CD115, were reported to more precisely define the MDSC subpopulation with suppressive function on T cells. [4][5][6] Recently, 2 subpopulations within Gr-1 ϩ CD11b ϩ MDSCs were described. 7 Ly6G ϩ with high side light scattering properties (SSC high ) and Ly6G Ϫ with low side light scattering properties (SSC low ) MDSCs were designated as polymorphonuclear MDSCs (PMN-MDSCs) and mononuclear MDSCs (MOMDSCs), respectively. 7 The majority of the MO-MDSCs expressed the monocyte/macrophage marker F4/80. A small number of cells expressing CD11b and Gr-1 is also detectable in blood and spleens of naive mice. [8][9][10] However, this cell population isolated from naive mice suppresses T-cell proliferation to a much lesser extent. 8,9 So far, all surface markers proposed for the phenotypical characterization of MDSCs are not only expressed by MDSCs but are also present on other cell types in naive or tumor-bearing mice. A marker exclusively expressed on MDSCs has not been defined.It is well established that MDSCs potently suppress antigen or ConA-induced T-cell proliferation and production of IFN-␥ and IL-2. 9,11-13 The mechanisms of this inhibition are not completely understood. It was reported that nitric oxide (NO) produced by MDSCs inhibits T-cell proliferation. 14,15 Furthermore, MDSCs suppress T-cell proliferation by down-regulation of surface expression of the CD3 chain via reactive oxygen species (ROS). 16 Recently, Nagaraj et al 12 demonstrated that ROS and peroxynitrite produced by MDSCs inhibit CD8 ϩ T-cell proliferation by interfering with TCR-mediated recognition of peptide-loaded MHC class I molecules.Natural killer (NK) cells, which are cytolytic and cytokineproducing effector cells, serve as a first line of immune defense against tumors. Their activation is determined by a delicate balance between inhibitory receptors, most of which are specific for self-MHC class I molecules, and activating receptors. 17 The activating receptor NKG2D, which in mice recognizes H60, and MULT1,[18][19][...
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