SUMMARY Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8+ T cell immunity and promoted CD4+Foxp3+ Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages in vivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN+ suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic.

The leukocyte immunoglobulin-like receptor (LILR) family comprises a set of paired immunomodulatory receptors expressed among human myeloid and lymphocyte cell populations. While six members of LILR subfamily A (LILRA) associate with membrane adaptors to signal via immunoreceptor tyrosine-based activating motifs (ITAM), LILR subfamily B (LILRB) members signal via multiple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIM). Ligand specificity of some LILR family members has been studied in detail, but new perspective into the immunoregulatory aspects of this receptor family in human myeloid cells has been limited. LILRB receptors and the murine ortholog, paired immunoglobulin-like receptor B (PIRB), have been shown to negatively regulate maturation pathways in myeloid cells including mast cells, neutrophils, dendritic cells, as well as B cells. Our laboratory further demonstrated in mouse models that PIRB regulated functional development of myeloid-derived suppressor cell and the formation of a tumor-permissive microenvironment. Based on observations from the literature and our own studies, our laboratory is focusing on how LILRs modulate immune homeostasis of human myeloid cells and how these pathways may be targeted in disease states. Integrity of this pathway in tumor microenvironments, for example, permits a myeloid phenotype that suppresses antitumor adaptive immunity. This review presents the evidence supporting a role of LILRs as myeloid cell regulators and ongoing efforts to understand the functional immunology surrounding this family.

Purpose The clinical effects of sunitinib on human myeloid-derived suppressor cell (MDSC) subsets and correlation of the T-cell–mediated immune responses and clinical outcomes in patients with oligometastases treated by stereotactic body radiotherapy (SBRT) have been evaluated. Experimental Design The numbers of granulocytic and monocytic MDSC subsets, effector T cells, and regulatory T cells in the peripheral blood were evaluated pre- and post-sunitinib treatment and concurrent with SBRT. Correlations between MDSC, Treg, and T-cell responses and clinical outcomes were analyzed. Results Patients with oligometastases of various cancer types had elevated granulocytic MDSC and certain subsets of monocytic MDSC population. Sunitinib treatment resulted in a significant reduction in monocytic MDSC, phosphorylated STAT3, and arginase levels in monocytic MDSC (CD33+CD14+CD16+), and an increase in T-cell proliferative activity in cancer patients. Interestingly, the effects of sunitinib on reducing the accumulation and immune-suppressive function of MDSC were significantly correlated with Treg reduction, in responders but not in nonresponding patients. SBRT synergized the therapeutic effects of sunitinib, especially as related to decreased numbers of monocytic MDSC, Treg, and B cells, and augmented Tbet expression in primary CD4 and CD8 T cells. These effects were not observed in patients receiving radiation therapy alone. Most interestingly, the responders, defined by sunitinib-mediated reduction in CD33+CD11b+ myeloid cell populations, tend to exhibit improved progression-free survival and cause-specific survival. Conclusions Sunitinib treatment increased the efficacy of SBRT in patients with oligometastases by reversing MDSC and Treg-mediated immune suppression and may enhance cancer immune therapy to prevent tumor recurrence post-SBRT.

One of the several impediments to effective oncolytic virus therapy of cancer remains a lack of tumor-specific targeting. Myeloid derived suppressor cells (MDSCs) are immature myeloid cells induced by tumor factors in tumor-bearing hosts. The biodistribution kinetics of MDSC and other immune cell types in a murine hepatic colon cancer model was investigated through the use of tracking markers and magnetic resonance imaging (MRI). MDSCs were superior to other immune cell types in preferential migration to tumors in comparison to other tissues. Based on this observation, we engineered a strain of vesicular stomatitis virus (VSV), an oncolytic rhabdovirus, that bound MDSCs and used them as a delivery vehicle. Improving VSV binding efficiency to MDSCs extended the long-term survival of mice bearing metastatic colon tumors, compared to systemic administration of wild-type VSV alone. Survival was further extended by multiple injections of the engineered virus without significant toxicity. Notably, direct tumor killing was accentuated by promoting MDSC differentiation towards the classically activated M1-like phenotype. Our results offer a preclinical proof of concept for using MDSCs to facilitate and enhance the tumor-killing activity of tumor-targeted oncolytic therapeutics.

Graft-versus-host disease (GVHD) is a major barrier to the widespread use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for treating hematologic malignancies. Myeloid-derived suppressor cells (MDSCs) have been recognized as crucial immunosuppressive cells in various pathologic settings. Here, we investigated whether the unique functional properties of MDSCs could be harnessed to control allo-HSCT-associated GVHD. Using multiple murine GVHD/GVL models including both MHC-mismatched and miHA-mismatched, we demonstrated that treatment with CD115+ MDSCs efficiently suppressed GVHD but did not significantly impair graft-versus-leukemia (GVL) activity, leading to 80% and 67% protection in treated mice in GVHD and GVL models, respectively. The mechanism for this dissociation of GVHD from GVL, specifically the emergence of donor-derived NKG2D + CD8 T cells with a memory phenotype in MDSC-treated recipient mice, was identified. NKG2D expression on donor T cells was required for eradication of allogeneic lymphoma cells. Furthermore, long-term surviving MDSC recipients that exhibited cytolytic activities against allogeneic leukemia cells had a significantly increased percentage of T regulatory cells and, more importantly, NKG2D + CD8 T cells. These findings indicate that MDSCs can be used as a novel cell-based therapy to suppress GVHD while maintaining GVL activities through selective induction of NKG2D + CD8 memory T cells.

The purpose of this study was to evaluate the recurrence rate and medical expenses of acute myocardial infarction (AMI) following inpatient cardiac rehabilitation. A total of 834 patients with AMI were divided into Group 1 (with inpatient cardiac rehabilitation) and Group 2 (without inpatient cardiac rehabilitation). The results showed that Group 1 had a lower AMI recurrence rate (a 0.640-fold lower hazards ratio) than Group 2 [95% confidence interval (CI) = 0.197-1.863; p = 0.004]. Compared with the medical costs of Group 2, Group 1 also had lower medical costs (a 0.947-fold lower hazards ratio) than Group 2 (95% CI = 0.934-0.981; p = 0.042). These findings have implications for the decision making of clinicians and health policymakers attempting to provide adequate services for patients with AMI.

We have recently demonstrated that oncolytic vesicular stomatitis viruses can be efficiently and selectively delivered to neoplastic lesions by myeloid-derived suppressor cells (MDSCs). Importantly, the loading of viruses onto MDSCs inhibited their immunosuppressive properties and endowed them with immunostimulatory and tumoricidal functions. Our study demonstrates the potential use of MDSCs as a Trojan horse for the tumor-targeted delivery of various anticancer therapeutics.

A rapid method based on high performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS) with accelerated solvent extraction (ASE) or solid phase extraction (SPE) was developed for quantitative determination of perfluorooctane sulfonate (PFOS) in the coatings of nonstick pot, food packaging materials, waterborne coatings containing fluoride and fire-fighting foams. The linear calibration curve was obtained in the range of 0.002 - 0.1 μg/mL with a linear correlation coefficient (R2) of 0.998 or 0.999. The recovery for PFOS was in the range of 93.4 - 103% with relative standard deviation of 0.48 - 3.59%. The detection limit for PFOS was 0.4 μg/m2 with a signal-to-noise ratio of 10 for the coatings of nonstick pot and the food packaging materials, and 0.0002% for waterborne coatings containing fluoride and fire-fighting foams, both of which meet the restriction requirement for PFOS content in these chemical materials and consumer products in the EU directives.