Due to our extensive coverage of the AACR21 conference, we will not include any spotlights this week. We'll bring them back next Wednesday!
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In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC)
Immunotherapy via immune checkpoints blockade has aroused the attention of researchers worldwide. Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has been one of the most promising immunotherapy strategies. Several neutralizing antibodies targeting this interaction have been developed, which have already achieved considerable clinical success. Additionally, numerous pharmaceutical companies have been committed to develop small molecules which could block the interaction between PD-1 and PD-L1. In this study, a novel PROTAC molecule 21a was developed, and effectively induced the degradation of PD-L1 protein in various malignant cells in a proteasome-dependent manner. Moreover, compound 21a could significantly reduce PD-L1 protein levels of MC-38 cancer cells in vivo, by which promoted the invasion of CD8(+) T cells and inhibited the growth of MC-38 in vivo. This PROTAC molecule could be used as a novel and alternative strategy for cancer immunotherapy.
Author Info: (1) The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. (2) The State Key Laboratory of Medicinal Chemical Bio
Author Info: (1) The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. (2) The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. (3) The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. (4) The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. (5) The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. (6) The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. (7) The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. (8) The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. (9) Tianjin Pacific Chemical & Pharmaceutical Co., LTD, Tianjin 300350, PR China. (10) Tianjin Pacific Chemical & Pharmaceutical Co., LTD, Tianjin 300350, PR China. (11) Cangzhou Institutes for Food and Drug Control, Cangzhou 061000, PR China. (12) Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, PR China. Electronic address: jwang05@tmu.edu.cn. (13) The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: mingmingshengwu@163.com. (14) The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: Guang.yang@nankai.edu.cn. (15) The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China.
Beyond PD-L1: B7-H6 emerges as a potential immunotherapy target in small cell lung cancer
INTRODUCTION: The PD-L1 immune checkpoint inhibitors atezolizumab and durvalumab have received regulatory approval for the first-line treatment of patients with extensive-stage small cell lung cancer. However, when used in combination with platinum-based chemotherapy, these PD-L1 inhibitors only improve overall survival by 2-3 months. This may be due to the observation that <20% of SCLC tumors express PD-L1 at >1%. Evaluating the composition and abundance of checkpoint molecules in SCLC may identify molecules beyond PD-L1 that are amenable to therapeutic targeting. METHODS: We analyzed RNA-Seq data from SCLC cell lines (n=108) and primary tumor specimens (n=81) for expression of 39 functionally validated, inhibitory checkpoint ligands. Further, we generated tissue microarrays containing SCLC cell lines and SCLC patient specimens to confirm expression of these molecules by immunohistochemistry. We annotated patient outcomes data, including treatment response and overall survival. RESULTS: The checkpoint protein B7-H6 (NCR3LG1) exhibited increased protein expression relative to PD-L1 in cell lines and tumors (P < 0.05). Higher B7-H6 protein expression correlated with longer progression-free survival (P = 0.0368) and increased total immune infiltrates (CD45+) in patients. Furthermore, increased B7-H6 gene expression in SCLC tumors correlated with a decreased activated NK cell gene signature, suggesting a complex interplay between B7-H6 expression and immune signature in SCLC. CONCLUSIONS: We investigated 39 inhibitory checkpoint molecules in SCLC and found that B7-H6 is highly expressed and associated with progression-free survival. In addition, 26/39 immune checkpoint proteins in SCLC tumors were more abundantly expressed than PD-L1, indicating an urgent need to investigate additional checkpoint targets for therapy in addition to PD-L1.
Author Info: (1) Department of Microbiology, Immunology, and Physiology, School of Medicine; School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA. (2) Department
Author Info: (1) Department of Microbiology, Immunology, and Physiology, School of Medicine; School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA. (2) Department of Biochemistry, Vanderbilt University, Nashville, TN, USA. (3) Division of Hematology-Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (4) Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA. (5) Breast Cancer Research Program, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA. (6) Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. (7) Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. (8) Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA. (9) Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA. (10) Department of Pathology, Immunology, and Microbiology, Vanderbilt University Medical Center, Nashville, TN, USA. (11) Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA. (12) Department of Pathology, Immunology, and Microbiology, Vanderbilt University Medical Center, Nashville, TN, USA. (13) Division of Hematology-Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (14) Division of Hematology-Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (15) Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. (16) Department of Biochemistry, Vanderbilt University, Nashville, TN, USA. (17) Department of Biochemistry, Vanderbilt University, Nashville, TN, USA. (18) Division of Hematology-Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (19) School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA; Division of Hematology-Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: christine.lovly@vumc.org.
Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET
A bispecific antibody (BsAb) targeting the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) pathways represents a novel approach to overcome resistance to targeted therapies in patients with non-small cell lung cancer. In this study, we sequentially screened a panel of BsAbs in a combinatorial approach to select the optimal bispecific molecule. The BsAbs were derived from different EGFR and MET parental monoclonal antibodies (mAbs). Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity towards MET. Hits were identified and further screened based on their potential to induce untoward cell proliferation and cross-phosphorylation of EGFR by MET via receptor colocalization in the absence of ligand. After the final step, we selected the EGFR and MET arms for the lead BsAb and added low fucose Fc engineering to generate amivantamab (JNJ-61186372). The crystal structure of the anti-MET Fab of amivantamab bound to MET was solved and elucidated the interaction between the two molecules in atomic details. Amivantamab antagonized the hepatocyte growth factor (HGF)-induced signaling by binding to MET Sema domain and thereby blocking HGF _-chain - Sema engagement. The amivantamab EGFR epitope was mapped to EGFR domain III and residues K443, K465, I467, and S468. Furthermore, amivantamab showed superior antitumor activity over small molecule EGFR and MET inhibitors in the HCC827-HGF in vivo model. Based on its unique mode of action, amivantamab may provide benefit to patients with malignancies associated with aberrant EGFR and MET signaling.
Author Info: (1) Genmab, Utrecht, The Netherlands. (2) Janssen Research & Development, Spring House, PA, USA. (3) Janssen Research & Development, Spring House, PA, USA. (4) Genmab, Utrecht, The
Author Info: (1) Genmab, Utrecht, The Netherlands. (2) Janssen Research & Development, Spring House, PA, USA. (3) Janssen Research & Development, Spring House, PA, USA. (4) Genmab, Utrecht, The Netherlands. (5) Section for Stem Cell Transplantation and Immunotherapy, Department of Medicine II, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany. (6) Janssen Research & Development, Spring House, PA, USA. (7) Janssen Research & Development, Spring House, PA, USA. (8) Genmab, Utrecht, The Netherlands. (9) Genmab, Utrecht, The Netherlands. (10) Janssen Research & Development, Spring House, PA, USA. (11) Janssen Research & Development, Spring House, PA, USA. Electronic address: markchiu03@gmail.com.
Myeloid-derived suppressor cells (MDSC) are important immune-regulatory cells but their identification remains difficult. Here, we provide a critical view on selected surface markers, transcriptional and translational pathways commonly used to identify MDSC by specific, their developmental origin and new possibilities by transcriptional or proteomic profiling. Discrimination of MDSC from their non-suppressive counterparts is a prerequisite for the development of successful therapies. Understanding the switch mechanisms that direct granulocytic and monocytic development into a pro-inflammatory or anti-inflammatory direction will be crucial for therapeutic strategies. Manipulation of these myeloid checkpoints are exploited by tumors and pathogens, such as M. tuberculosis (Mtb), HIV or SARS-CoV-2, that induce MDSC for immune evasion. Thus, specific markers for MDSC identification may reveal also novel molecular candidates for therapeutic intervention at the level of MDSC.
Author Info: (1) Institute for Virology and Immunobiology, University of Wrzburg, Wrzburg, Germany. Electronic address: m.lutz@vim.uni-wuerzburg.de. (2) Institute for Virology and Immunobiolo
Author Info: (1) Institute for Virology and Immunobiology, University of Wrzburg, Wrzburg, Germany. Electronic address: m.lutz@vim.uni-wuerzburg.de. (2) Institute for Virology and Immunobiology, University of Wrzburg, Wrzburg, Germany.
The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression
BACKGROUND: Immune checkpoint inhibitors (ICIs) are essential for treatment of various malignancies, including non-small-cell lung cancer (NSCLC). Recently, several studies have shown that the gut microbiome plays an important role in ICI treatment of solid cancers, and antibiotic (ATB) use had a negative impact on the outcomes of ICI treatment via dysbiosis in the gut. However, whether this is applicable to NSCLC remains unclear. The impact of ATBs based on PD-L1 expression also remains unclear. METHODS: We retrospectively reviewed the medical records of patients with NSCLC who received ICI monotherapy (anti-PD-1 or anti-PD-L1 antibody) at nine institutions from December 2015 to May 2018. Outcomes with use of ATBs during the 2 months before or a month after initiation of ICI treatment, including progression-free survival (PFS) and overall survival (OS), were investigated using the Kaplan-Meier method. Multivariate analysis was also conducted using a Cox proportional hazards model. RESULTS: A total of 531 patients were included in this study, among whom 98 (18.5%) received ATBs before or after ICI treatment. ATB use was significantly associated with a shorter median OS (11.7 months in the ATB group vs. 16.1 months in the non-ATB group; p = 0.028), whereas the difference in PFS was not significant (3.5 months in both the groups; p = 0.287). We next investigated the association based on PD-L1 expression in the 265 patients for whom PD-L1 expression was determined. There was no significant difference in the median OS or PFS between patients with NSCLC and PD-L1 expression <50% receiving ATBs and those not receiving ATBs (PFS: 3.3 vs. 2.8 months, p = 0.88; OS: 9.5 vs. 17.1 months, p = 0.24). Conversely, patients with NSCLC and PD-L1 expression ³50% receiving ATBs showed significantly shorter median PFS and OS (PFS: 4.2 vs. 9.4 months, p = 0.012; OS: 11.9 vs. 28.4 months, p = 0.011). The impact of ATBs in patients with NSCLC and PD-L1 expression ³50% was more significant than that in the entire cohort. CONCLUSIONS: Our results indicate that the impact of ATB use on the efficacy of ICIs differed based on PD-L1 expression in patients with advanced NSCLC. A negative impact of ATB use was found in patients with NSCLC and PD-L1 expression ³50% but not in those with PD-L1 expression <50%.
Author Info: (1) Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan. (2) Department of Allergy and Respiratory Medicine, Okayama University Hospital, Japan. Elec
Author Info: (1) Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan. (2) Department of Allergy and Respiratory Medicine, Okayama University Hospital, Japan. Electronic address: ichiha-e@md.okayama-u.ac.jp. (3) Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan. (4) Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Japan. (5) Department of Respiratory Medicine, Ehime Prefectural Central Hospital, Japan. (6) Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Japan. (7) Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Japan. (8) Department of Respiratory Medicine, Himeji Red Cross Hospital, Japan. (9) Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan. (10) Department of Internal Medicine, Fukuyama City Hospital, Japan. (11) Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan. (12) Center for Innovative Clinical Medicine, Okayama University Hospital, Japan. (13) Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan. (14) Department of Allergy and Respiratory Medicine, Okayama University Hospital, Japan.
High-throughput identification of conditional MHCI ligands and scaled-up production of conditional MHCI complexes
Despite the need to monitor the impact of Cancer Immunotherapy (CI)/Immuno-Oncology (IO) therapeutics on neoantigen-specific T-cell responses, very few clinical programs incorporate this aspect of immune monitoring due to the challenges in high-throughput (HTP) generation of MHCI tetramers across a wide range of HLA alleles. This limitation was recently addressed through the development of MHCI complexes with peptides containing a non-natural UV cleavable amino acid (conditional MHCI ligands) that enabled HTP peptide exchange upon UV exposure. Despite this advancement, the number of alleles with known conditional MHCI ligands is limited. We developed a novel workflow to enable identification and validation of conditional MHCI ligands across a range of HLA alleles. First, known peptide binders were screened via an ELISA assay. Conditional MHCI ligands were designed using the highest-performing peptides and evaluated in the same ELISA assay.The top performers were then selected for scale-up production. Next-generation analytical techniques (LC/MS, SEC-MALS and 2D LC/MS) were used to characterize the complex after refolding with the conditional MHCI ligands. Finally, we used 2D LC/MS to evaluate peptide exchange with these scaled-up conditional MHCI complexes after UV exposure with validated peptide binders. Successful peptide exchange was observed for all conditional MHCI ligands upon UV exposure, validating our screening approach. This approach has the potential to be broadly applied and enable HTP generation of MHCI monomers and tetramers across a wider range of HLA alleles, which could be critical to enabling the use of MHCI tetramers to monitor neoantigen-specific T-cells in the clinic. This article is protected by copyright. All rights reserved.
Author Info: (1) Genentech Inc, Protein Chemistry. (2) Genentech Inc, Protein Chemistry. (3) Genentech Inc, Biochemical and Cellular Pharmacology. (4) Genentech Inc, Protein Chemistry. (5) Gene
Author Info: (1) Genentech Inc, Protein Chemistry. (2) Genentech Inc, Protein Chemistry. (3) Genentech Inc, Biochemical and Cellular Pharmacology. (4) Genentech Inc, Protein Chemistry. (5) Genentech Inc, BioMolecular Resources. (6) Genentech Inc, BioMolecular Resources. (7) Genentech Inc, Protein Chemistry. (8) Genentech Inc, Biochemical and Cellular Pharmacology. (9) Genentech Inc.
Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade
The mechanisms behind the antitumor effects of exercise training (ExTr) are not fully understood. Using mouse models of established breast cancer (BC), we examined here the causal role of CD8+ T cells in the benefit acquired from ExTr in tumor control, as well as the ability of ExTr to improve immunotherapy responses. We implanted E0771, EMT6, MMTV-PyMT, and MCa-M3C BC cells orthotopically in wild-type or Cxcr3-/- female mice and initiated intensity-controlled ExTr sessions when tumors reached ~100 mm3. We characterized the tumor microenvironment (TME) using flow cytometry, transcriptome analysis, proteome array, ELISA, and immunohistochemistry. We used antibodies against CD8+ T cells for cell depletion. Treatment with immune checkpoint blockade (ICB) consisted of anti-PD-1 alone or in combination with anti-CTLA-4. ExTr delayed tumor growth and induced vessel normalization, demonstrated by increased pericyte coverage and perfusion, and decreased hypoxia. ExTr boosted CD8+ T-cell infiltration, with enhanced effector function. CD8+ T-cell depletion prevented the antitumor effect of ExTr. The recruitment of CD8+ T cells and the antitumor effects of ExTr were abrogated in Cxcr3-/- mice, supporting the causal role of the CXCL9/CXCL11-CXCR3 pathway. ExTr also sensitized ICB-refractory BCs to treatment. Our results indicate that ExTr can normalize the tumor vasculature, reprogram the immune TME, and enhance the antitumor activity mediated by CD8+ T cells via CXCR3, boosting ICB responses. Our findings and mechanistic insights provide a rationale for the clinical translation of ExTr to improve immunotherapy of BC.
Author Info: (1) Radiation Oncology, Massachusetts General Hospital & Harvard Medical School. (2) Massachusetts General Hospital. (3) Radiation Oncology, Massachusetts General Hospital & Harvar
Author Info: (1) Radiation Oncology, Massachusetts General Hospital & Harvard Medical School. (2) Massachusetts General Hospital. (3) Radiation Oncology, Massachusetts General Hospital & Harvard Medical School. (4) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital. (5) Radiation Oncology, Massachusetts General Hospital & Harvard Medical School. (6) Cancer Center, Massachusetts General Hospital. (7) Radiation Oncology, Massachusetts General Hospital & Harvard Medical School. (8) Department of Breast Surgery, Kyoto University. (9) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School. (10) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School dai@steele.mgh.harvard.edu.
Yeasts as a promising delivery platform for DNA and RNA vaccines
Yeasts are considered a useful system for the development of vaccines for human and veterinary health. Species such as Saccharomyces cerevisiae and Pichia pastoris have been used successfully as host organisms for the production of subunit vaccines. These organisms have been also explored as vaccine vehicles enabling the delivery of antigens such as proteins and nucleic acids. The employed species possess a GRAS status (Generally Recognized as Safe) for the production of therapeutic proteins, besides promoting immunostimulation due to the properties of their wall cell composition. This strategy allows the administration of nucleic acids orally and a specific delivery to professional antigen-presenting cells (APCs). In this review, we seek to outline the development of whole yeast vaccines (WYV) carrying nucleic acids in different approaches in the medical field, as well as the immunological aspects of this vaccine strategy. The data presented here reveal the application of this platform in promoting effective immune responses in the context of prophylactic and therapeutic approaches.
Author Info: (1) Laboratrio de Estudos Moleculares e Terapia Experimental, Department of Genetics, Federal University of Pernambuco, Av. Prof. Moraes Rgo, 1235, Cidade Universitaria, Recife,
Author Info: (1) Laboratrio de Estudos Moleculares e Terapia Experimental, Department of Genetics, Federal University of Pernambuco, Av. Prof. Moraes Rgo, 1235, Cidade Universitaria, Recife, Pernambuco, Brazil. (2) Laboratrio de Estudos Moleculares e Terapia Experimental, Department of Genetics, Federal University of Pernambuco, Av. Prof. Moraes Rgo, 1235, Cidade Universitaria, Recife, Pernambuco, Brazil. (3) Laboratrio de Estudos Moleculares e Terapia Experimental, Department of Genetics, Federal University of Pernambuco, Av. Prof. Moraes Rgo, 1235, Cidade Universitaria, Recife, Pernambuco, Brazil. (4) Laboratrio de Estudos Moleculares e Terapia Experimental, Department of Genetics, Federal University of Pernambuco, Av. Prof. Moraes Rgo, 1235, Cidade Universitaria, Recife, Pernambuco, Brazil. (5) Laboratrio de Estudos Moleculares e Terapia Experimental, Department of Genetics, Federal University of Pernambuco, Av. Prof. Moraes Rgo, 1235, Cidade Universitaria, Recife, Pernambuco, Brazil.
T cell memory in tissues
Immunological memory equips our immune system to respond faster and more effectively against reinfections. This acquired immunity was originally attributed to long-lived, memory T and B cells with body wide access to peripheral and secondary lymphoid tissues. In recent years, it has been realized that both innate and adaptive immunity to a large degree depends on resident immune cells that act locally in barrier tissues, including tissue resident memory T cells (Trm). Here, we will discuss the phenotype of these Trm in mice and humans, the tissues and niches that support them, and their function, plasticity and transcriptional control. Their unique properties enable Trm to achieve long-lived immunological memory that can be deposited in nearly every organ in response to acute and persistent infection, and in response to cancer. However, Trm may also induce substantial immunopathology in allergic and autoimmune disease if their actions remain unchecked. Therefore, inhibitory and activating stimuli appear to balance the actions of Trm to ensure rapid pro-inflammatory responses upon infection and to prevent damage to host tissues under steady state conditions. This article is protected by copyright. All rights reserved.
Author Info: (1) Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Department of Experimental Immunol
Author Info: (1) Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. (2) Viral Immunobiology, University of Zurich, Zurich, Switzerland. Epidemiology, Biostatistics and Prevention Institute, Department of Public and Global Health, University of Zurich, Zurich, Switzerland. Department of Infectious Diseases and Hospital Epidemiology, University Hospital, Zurich, Switzerland. (3) Viral Immunobiology, University of Zurich, Zurich, Switzerland.
Comments on the ambiguity of selected surface markers, signaling pathways and omics profiles hampering the identification of myeloid-derived suppressor cells