Suppressor Cells In Cancer Patients Research Articles

Pituitary hormone α-MSH promotes tumor-induced myelopoiesis and immunosuppression.

The hypothalamic-pituitary (HP) unit can produce various hormones to regulate immune responses, and some of its downstream hormones or effectors are elevated in cancer patients. We show that the HP unit can promote myelopoiesis and immunosuppression to accelerate tumor growth. Subcutaneous implantation of tumors induced hypothalamus activation and pituitary α-melanocyte-stimulating hormone (α-MSH) production in mice. α-MSH acted on bone marrow progenitors to promote myelopoiesis, myeloid cell accumulation, immunosuppression, and tumor growth through its melanocortin receptor MC5R. MC5R peptide antagonist boosted antitumor immunity and anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. Serum α-MSH concentration was elevated and correlated with circulating myeloid-derived suppressor cells in cancer patients. Our results reveal a neuroendocrine pathway that suppresses tumor immunity and suggest MC5R as a potential target for cancer immunotherapy.

Analysis of classical neutrophils and polymorphonuclear myeloid-derived suppressor cells in cancer patients and tumor-bearing mice.

In this study, using single-cell RNA-seq, cell mass spectrometry, flow cytometry, and functional analysis, we characterized the heterogeneity of polymorphonuclear neutrophils (PMNs) in cancer. We describe three populations of PMNs in tumor-bearing mice: classical PMNs, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and activated PMN-MDSCs with potent immune suppressive activity. In spleens of mice, PMN-MDSCs gradually replaced PMNs during tumor progression. Activated PMN-MDSCs were found only in tumors, where they were present at the very early stages of the disease. These populations of PMNs in mice could be separated based on the expression of CD14. In peripheral blood of cancer patients, we identified two distinct populations of PMNs with characteristics of classical PMNs and PMN-MDSCs. The gene signature of tumor PMN-MDSCs was similar to that in mouse activated PMN-MDSCs and was closely associated with negative clinical outcome in cancer patients. Thus, we provide evidence that PMN-MDSCs are a distinct population of PMNs with unique features and potential for selective targeting opportunities.

Cisplatin inhibits frequency and suppressive activity of monocytic myeloid-derived suppressor cells in cancer patients

ABSTRACT Cancer immunotherapies have induced long-lasting responses in cancer patients including those with melanoma and head and neck squamous cell carcinoma (HNSCC). However, the majority of treated patients does not achieve clinical benefit from immunotherapy because of systemic tumor-induced immunosuppression. Monocytic myeloid-derived suppressor cells (M-MDSCs) are implicated as key players in inhibiting anti-tumor immune responses and their frequencies are closely associated with tumor progression. Tumor-derived signals, including signaling via STAT3-COX-2, induce the transformation of monocytic precursors into suppressive M-MDSCs. In a retrospective assessment, we observed that survival of melanoma patients undergoing dendritic cell vaccination was negatively associated with blood M-MDSC levels. Previously, it was shown that platinum-based chemotherapeutics inhibit STAT signaling. Here, we show that cisplatin and oxaliplatin treatment interfere with the development of M-MDSCs, potentially synergizing with cancer immunotherapy. In vitro, subclinical doses of platinum-based drugs prevented the generation of COX-2+ M-MDSCs induced by tumor cells from melanoma patients. This was confirmed in HNSCC patients where intravenous cisplatin treatment drastically lowered M-MDSC frequency while monocyte levels remained stable. In treated patients, expression of COX-2 and arginase-1 in M-MDSCs was significantly decreased after two rounds of cisplatin, indicating inhibition of STAT3 signaling. In line, the capacity of M-MDSCs to inhibit activated T cell responses ex vivo was significantly decreased after patients received cisplatin. These results show that platinum-based chemotherapeutics inhibit the expansion and suppressive activity of M-MDSCs in vitro and in cancer patients. Therefore, platinum-based drugs have the potential to enhance response rates of immunotherapy by overcoming M-MDSC-mediated immunosuppression.

The analysis of myeloid-derived suppressor cells in cancer patients with neutropenia to evaluate the effect of granulocytes colony stimulation factor

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population associated with immunosuppression andinflammation in cancer patients. Granulocytes colony stimulating factor (G-CSF) is frequently used in cancer patients withneutropenia. To evaluate the effect of G-CSF on patients being chemotherapy, we analyzed MDSCs in the peripheral blood.Peripheral blood was collected from 13 patients accompanied neutropenia during chemotherapy before and after G-CSFadministration. Flow cytometry was used to examine the percentage of MDSCs. The changes of MDSCs in the peripheral bloodaccording to G-CSF infusion were analyzed. The absolute neutrophil counts in patients before G-CSF administration were560±353 cells/uL (59-1,102 cells/uL). MDSCs were detected in the peripheral mononuclear cells with a cell percentage of2.74±4.02% (0.2-12.2%) and 5.48±8.56% (0.2-26.9%) before and after G-CSF infusion, respectively. Although there is nostatistically significance, G-CSF generally seems to move the MDSCs from the bone marrow to the peripheral blood to increaseMDSCs in the peripheral blood. It is necessary to study how the increased MDSCs affect the patient’s prognosis.

Abstract CT095: The selective targeting of myeloid-derived suppressor cells in cancer patients using an agonistic TRAIL-R2 antibody

Abstract The goal of this current study was to clinically test the hypothesis that by targeting TRAIL-R2, myeloid-derived suppressor cells (MDSCs) can be selectively eliminated. MDSC) are one of the major contributors to immune suppression in cancer. We previously demonstrated in a preclinical study that MDSCs are sensitive to a TRAIL receptor 2 (TRAIL-R2) agonist. The TRAIL-R2 agonistic antibody (DS-8273a; provided by Daiichi Sankyo, Inc.) was tested in 16 patients with advanced solid cancers or lymphomas enrolled in a phase 1 trial. The antibody (24 mg/kg) was administered IV once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated using flow cytometry and immunohistochemistry. Overall, the treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Furthermore, treatment with DS-8273a resulted in reduction of the elevated numbers of MDSC in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSC rebounded back to the pre-treatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells with decreases in MDSC levels inversely correlating with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSC in 50% of the patients who were able to provide pre- and on-treatment biopsies. In conclusion, targeting TRAIL-R2 using DS-8273a resulted in a temporary elimination of MDSCs without affecting mature myeloid or lymphoid cells, and these data support further use of this antibody in combination with current immmunotherapies of cancer. Citation Format: George A. Dominguez, Thomas Condamine, Sridevi Mony, Ayumi Hashimoto, Fang Wang, Qin Liu, Andres Forero, Johanna C. Bendell, Robert Witt, Neil Hockstein, Prasanna Kumar, Dmitry I. Gabrilovich. The selective targeting of myeloid-derived suppressor cells in cancer patients using an agonistic TRAIL-R2 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT095. doi:10.1158/1538-7445.AM2017-CT095

The clinical evidence for targeting human myeloid-derived suppressor cells in cancer patients.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that represent a formidable obstacle to the successful treatment of cancer. Patients with high frequencies of MDSCs have significantly decreased progression-free survival (PFS) and overall survival (OS). Whereas there is experimental evidence that the reduction of the number and/or suppressive function of MDSCs in mice improves the efficacy of anti-cancer therapies, there is notably less evidence for this therapeutic strategy in human clinical trials. Here, we discuss currently available data concerning MDSCs from human clinical trials and explore the evidence that targeting MDSCs may improve the efficacy of cancer therapies.

Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients.

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are important regulators of immune responses in cancer and have been directly implicated in promotion of tumor progression. However, the heterogeneity of these cells and lack of distinct markers hampers the progress in understanding of the biology and clinical importance of these cells. Using partial enrichment of PMN-MDSC with gradient centrifugation we determined that low density PMN-MDSC and high density neutrophils from the same cancer patients had a distinct gene profile. Most prominent changes were observed in the expression of genes associated with endoplasmic reticulum (ER) stress. Surprisingly, low-density lipoprotein (LDL) was one of the most increased regulators and its receptor oxidized LDL receptor 1 OLR1 was one of the most overexpressed genes in PMN-MDSC. Lectin-type oxidized LDL receptor 1 (LOX-1) encoded by OLR1 was practically undetectable in neutrophils in peripheral blood of healthy donors, whereas 5-15% of total neutrophils in cancer patients and 15-50% of neutrophils in tumor tissues were LOX-1+. In contrast to their LOX-1- counterparts, LOX-1+ neutrophils had gene signature, potent immune suppressive activity, up-regulation of ER stress, and other biochemical characteristics of PMN-MDSC. Moreover, induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSC. Thus, we identified a specific marker of human PMN-MDSC associated with ER stress and lipid metabolism, which provides new insight to the biology and potential therapeutic targeting of these cells.

Interaction Between Invariant NKT Cells and Myeloid-derived Suppressor Cells in Cancer Patients

Despite advances in therapeutic strategies, the ability of cancer cells to evade destruction remains a significant obstacle to the development of effective anticancer treatment. In recent years a subset of immune cells, myeloid-derived suppressor cells (MDSCs), has been shown to play a key role in evasion of the patient's immune system by tumor cells. A number of different tumor types are associated with increased numbers of circulating MDSCs in cancer patients, suppressing the immune response and permitting continued tumor cell proliferation. Invariant NKT (iNKT) cells have recently been defined as a unique subset of immune cells that are able to act as a link between the innate and adaptive arms of the immune system. iNKT cells have the ability to carry out immune surveillance of tumor cells and control proliferation of malignant cells. Recently, we presented evidence that iNKT cells are able to interact with and decrease the numbers of circulating MDSCs in melanoma patients. This review discusses the evidence for MDSCs in tumor progression and the implication that iNKT cells could be developed as a potent therapeutic strategy.

Abstract LB-127: Identifying an IDO-expressing “fibrocyte” subset of myeloid suppressor cells in pediatric cancer patients

Abstract Human myeloid derived suppressor cells (MDSC) have been described as CD14-CD11b+CD33+HLADR- cells that exert T cell suppression via ROS, ARG1 and iNOS2. Here, we report a novel myeloid subset found within mononuclear fraction elutriated from apheresis samples of pediatric cancer patients vs. healthy controls. Of 60 pediatric cancer patients studied, we frequently observed expanded numbers of CD14-CD123-CD11chi cells, which were rare and found only at low levels in healthy donors. Like previously described MDSC, these cells were CD11b+, but CD33lo/-HLADR+. In addition, these abnormal myeloid cells were CD34+CD15+CD16+CD66b+CD68+PDL1+ and IL4Rα+. Interestingly they also expressed α smooth muscle actin and collagen I/V on their surface, which are hallmarks of fibrocytes. The fibrocytes expressed high levels of indoleamine oxidase (IDO), but did not express ARG1, ARG2, iNOS2. They suppressed T cell proliferation in response to OKT3, which was partially reversed by the addition of 1MT, an inhibitor of IDO. Given the IL4Rα expression, we sought to induce these cells in vitro from normal monocytes using IL-4. Indeed, IL4 alone was sufficient to drive monocytes to differentiate into fibrocytes, which demonstrate a spindle-like shape, adhere to plastic, acquire the CD11chiCD14-CD34+CD16+collagenI+ phenotype, and express IDO. Fibrocytes have previously been implicated in chronic inflammation, angiogenesis and wound healing. We conclude that they also constitute a novel subset of myeloid derived suppressor cells in cancer patients, and could contribute to tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-127. doi:1538-7445.AM2012-LB-127

Myeloid-derived Suppressor Cells in Cancer Patients

Myeloid-derived suppressor cells (MDSCs) represent a heterogenous collection of immature myeloid cells endowed with suppressive function on the immune response. Their presence has been extensively investigated in preclinical models, especially in the context of cancer. One of the major obstacles in their accurate identification has been the definition of an unambiguous phenotype, shared between mice and humans, and clearly correlating with their suppressive function. In this paper, we review the literature concerning the phenotype in mouse and in humans, showing that at least 2 subsets of MDSCs are present under different situations. We also address the role of MDSCs in tumor progression, evaluate the prognostic significance of MDSC in cancer patients, and their possible role as marker of clinical outcome and response to therapy. Finally, we examine the strategies designed to modulate MDSCs in cancer patients, which might represent an innovative approach to enhance the effectiveness of immune-based therapies.

Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients

The involvement of a smouldering microenvironment is currently considered a cancer hallmark and a required step for tumour cells to disable specific immunity while promoting angiogenesis and stroma remodelling. Nevertheless, the molecular pathways driving such aberrant interactions in human cancer and their actual implication in disease progression are still poorly defined. Here, we will report about the remarkable efforts devoted by our group as well as many other scientists to dissect this process focusing on tumour-mediated activation of myeloid dysfunctional pathways occurring in cancer patients. Indeed, myeloid-derived suppressor cells (MDSC), playing a crucial role as cellular regulators of immune responses, have been extensively shown to restrain tumour immunity through a vast array of molecular mechanisms and to promote tumour progression in different murine models. Although in mice the phenotypic features of these cells were defined initially rather generally by Gr1(+) and CD11b(+) co-expression, more recent studies have unravelled the actual complexity of this population and the existence of different cell subsets. This complexity is even more remarked in the human setting, where heterogeneous populations of myeloid cells with variable phenotype and immunosuppressive features have been described in patients affected by different types of tumours. The lack of homogeneous properties of human MDSC has made these cells a controversial and still unacknowledged player in cancer-related immune suppression and disease progression. Nevertheless, with the efforts of the scientific community, MDSC will soon reveal their key role thereby becoming novel targets for innovative therapeutic strategies.

Reduction of suppressor cells in cancer patients treated with OK-432 immunotherapy.

OK-432, a streptococcal preparation, was intradermally injected daily into patients with advanced cancer of the stomach or lung for 4 weeks and the effects of OK-432 on the mitogenic responses of cancer patients were followed. The cells involved in the depression of the response of untreated cancer patients were characterized. The cells responsible for impaired responses were nylon wool non-adherent and suppressed the mitogen responses of autologous and allogeneic lymphocytes. These cells lost their suppressive activity during 7 days' culture in vitro. Following OK-432 immunotherapy, mononuclear cells from cancer patients showed increased responses to PHA and Con A, and nylon wool non-adherent cells did not inhibit the mitogen responses. These results suggest that the cells suppressing non-specific mitogen responses are sensitive to in vitro culture, belong to nylon wool non-adherent cells and are lost during 4 weeks of OK-432 therapy.

Reduction of suppressor cells in cancer patients treated with OK-432

Reduction of suppressor cells in cancer patients treated with OK-432