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Immunophenotyping in Autoimmune Diseases and Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 64932

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Dr. Gábor J. Szebeni

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Biological Research Center of the Hungarian Academy of Sciences Temesvári krt. 62. Szeged, H-6726, Hungary
Special Issues, Collections and Topics in MDPI journals

Dr. László G. Puskás

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Biological Research Centre, Temesvári krt. 62, H-6726 Szeged, Hungary
Interests: immuno-oncology; in vitro diagnostics; single cell genomics; microarray technologies
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

The mammalian immune system is a Janus-faced network of well-coordinated, highly specialized cells and biomolecules. The sensitive balance of reactive and suppressive signals maintains homeostasis in the physiological state. Under pathological conditions, however, responsiveness can escalate in autoimmune diseases or remain suppressed in cancer. In severe autoimmunity, the overwhelming immune response leads to devastating diseases such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, sclerosis multiplex, etc. Conversely, immune cells, e.g., professional antigen-presenting cells, cytotoxic T cells, are not able to execute their physiological function in cancer.

Recent progress in fluorescence flow cytometry and mass cytometry has contributed to a high-dimensional resolution of the complex immunophenotype both in autoimmune diseases and in cancer. We would like to call authors to publish their latest achievements associated with the perturbance of the regulation of immune activation and the discovery of rare subpopulations of both innate and adaptive immune players in autoimmune diseases and cancer. This Special Issue will publish works presenting not only the description of different cellular subtypes but also the identification of novel key molecular factors. Submission of research articles is mainly expected. Because of the recent developments in high-content, multilevel profiling technologies, review articles from pioneer scientists can also be considered.

Dr. Gábor J. Szebeni
Dr. László G. Puskás
Guest Editors

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Keywords

immunophenotyping
immune regulation
multiparameter cytometry
immuno oncology
anti-tumor immunity
autoimmunity
cancer immunology

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Published Papers (9 papers)

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Research

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13 pages, 4499 KiB

Open AccessArticle

Syntaxin 1: A Novel Robust Immunophenotypic Marker of Neuroendocrine Tumors

by Bence Kővári, Sándor Turkevi-Nagy, Ágnes Báthori, Zoltán Fekete and László Krenács

Int. J. Mol. Sci. 2020, 21(4), 1213; https://doi.org/10.3390/ijms21041213 - 12 Feb 2020

Cited by 7 | Viewed by 3987

Abstract

Considering the specific clinical management of neuroendocrine (NE) neoplasms (NENs), immunohistochemistry (IHC) is required to confirm their diagnosis. Nowadays, synaptophysin (SYP), chromogranin A (CHGA), and CD56 are the most frequently used NE immunohistochemical markers; however, their sensitivity and specificity are less than optimal. Syntaxin 1 (STX1) is a member of a membrane-integrated protein family involved in neuromediator release, and its expression has been reported to be restricted to neuronal and NE tissues. In this study, we evaluated STX1 as an immunohistochemical marker of NE differentiation. STX1, SYP, CHGA, and CD56 expression was analyzed in a diverse series of NE tumors (NETs), NE carcinomas (NECs), and non-NE tumors. All but one (64/65; 98%) NETs and all (54/54; 100%) NECs revealed STX1 positivity in at least 50% of the tumor cells. STX1 showed the highest sensitivity both in NETs (99%) and NECs (100%) compared to CHGA (98% and 91%), SYP (96% and 89%), and CD56 (70% and 93%), respectively. A wide variety of non-NE tumors were tested and found to be uniformly negative, yielding a perfect specificity. We established that STX1 is a robust NE marker with an outstanding sensitivity and specificity. Its expression is independent of the site and grade of the NENs. Full article

(This article belongs to the Special Issue Immunophenotyping in Autoimmune Diseases and Cancer)

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10 pages, 1846 KiB

Open AccessArticle

A Small Number of HER2 Redirected CAR T Cells Significantly Improves Immune Response of Adoptively Transferred Mouse Lymphocytes against Human Breast Cancer Xenografts

by Gábor Tóth, János Szöllősi, Hinrich Abken, György Vereb and Árpád Szöőr

Int. J. Mol. Sci. 2020, 21(3), 1039; https://doi.org/10.3390/ijms21031039 - 4 Feb 2020

Cited by 32 | Viewed by 4585

Abstract

HER2 positive JIMT-1 breast tumors are resistant to trastuzumab treatment in vitro and develop resistance to trastuzumab in vivo in SCID mice. We explored whether these resistant tumors could still be eliminated by T cells redirected by a second-generation chimeric antigen receptor (CAR) containing a CD28 costimulatory domain and targeting HER2 with a trastuzumab-derived scFv. In vitro, T cells engineered with this HER2 specific CAR recognized HER2 positive target cells as judged by cytokine production and cytolytic activity. In vivo, the administration of trastuzumab twice weekly had no effect on the growth of JIMT-1 xenografts in SCID mice. At the same time, a single dose of 2.5 million T cells from congenic mice exhibited a moderate xenoimmune response and even stable disease in some cases. In contrast, when the same dose contained 7% (175,000) CAR T cells, complete remission was achieved in 57 days. Even a reduced dose of 250,000 T cells, including only 17,500 CAR T cells, yielded complete remission, although it needed nearly twice the time. We conclude that even a small number of CAR T lymphocytes can evoke a robust anti-tumor response against an antibody resistant xenograft by focusing the activity of xenogenic T cells. This observation may have significance for optimizing the dose of CAR T cells in the therapy of solid tumors. Full article

(This article belongs to the Special Issue Immunophenotyping in Autoimmune Diseases and Cancer)

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19 pages, 25528 KiB

Open AccessArticle

Single Cell Mass Cytometry Revealed the Immunomodulatory Effect of Cisplatin Via Downregulation of Splenic CD44+, IL-17A+ MDSCs and Promotion of Circulating IFN-γ+ Myeloid Cells in the 4T1 Metastatic Breast Cancer Model

by József Á. Balog, László Hackler Jr., Anita K. Kovács, Patrícia Neuperger, Róbert Alföldi, Lajos I. Nagy, László G. Puskás and Gábor J. Szebeni

Int. J. Mol. Sci. 2020, 21(1), 170; https://doi.org/10.3390/ijms21010170 - 25 Dec 2019

Cited by 38 | Viewed by 5850

Abstract

The treatment of metastatic breast cancer remained a challenge despite the recent breakthrough in the immunotherapy regimens. Here, we addressed the multidimensional immunophenotyping of 4T1 metastatic breast cancer by the state-of-the-art single cell mass cytometry (CyTOF). We determined the dose and time dependent cytotoxicity of cisplatin on 4T1 cells by the xCelligence real-time electronic sensing assay. Cisplatin treatment reduced tumor growth, number of lung metastasis, and the splenomegaly of 4T1 tumor bearing mice. We showed that cisplatin inhibited the tumor stroma formation, the polarization of carcinoma-associated fibroblasts by the diminished proteolytic activity of fibroblast activating protein. The CyTOF analysis revealed the emergence of CD11b+/Gr-1+/CD44+ or CD11b+/Gr-1+/IL-17A+ myeloid-derived suppressor cells (MDSCs) and the absence of B220+ or CD62L+ B-cells, the CD62L+/CD4+ and CD62L+/CD8+ T-cells in the spleen of advanced cancer. We could show the immunomodulatory effect of cisplatin via the suppression of splenic MDSCs and via the promotion of peripheral IFN-γ+ myeloid cells. Our data could support the use of low dose chemotherapy with cisplatin as an immunomodulatory agent for metastatic triple negative breast cancer. Full article

(This article belongs to the Special Issue Immunophenotyping in Autoimmune Diseases and Cancer)

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13 pages, 2747 KiB

Open AccessArticle

Toll-Like Receptor Mediated Activation of Natural Autoantibody Producing B Cell Subpopulations in an Autoimmune Disease Model

by Szabina Erdő-Bonyár, Judit Rapp, Tünde Minier, Gábor Ráth, József Najbauer, László Czirják, Péter Németh, Timea Berki and Diána Simon

Int. J. Mol. Sci. 2019, 20(24), 6152; https://doi.org/10.3390/ijms20246152 - 6 Dec 2019

Cited by 17 | Viewed by 3488

Abstract

Altered expression and function of the Toll-like receptor (TLR) homologue CD180 molecule in B cells have been associated with autoimmune disorders. In this study, we report decreased expression of CD180 at protein and mRNA levels in peripheral blood B cells of diffuse cutaneous systemic sclerosis (dcSSc) patients. To analyze the effect of CD180 stimulation, together with CpG (TLR9 ligand) treatment, on the phenotype defined by CD19/CD27/IgD/CD24/CD38 staining, and function (CD69 and CD180 expression, cytokine and antibody secretion) of B cell subpopulations, we used tonsillar B cells. After stimulation, we found reduced expression of CD180 protein and mRNA in total B cells, and CD180 protein in B cell subpopulations. The frequency of CD180⁺ cells was the highest in the CD19⁺CD27⁺IgD⁺ non-switched (NS) B cell subset, and they showed the strongest activation after anti-CD180 stimulation. Furthermore, B cell activation via CD180 induced IL-6 and natural autoantibody secretion. Treatment with the combination of anti-CD180 antibody and CpG resulted in increased IL-6 and IL-10 secretion and natural autoantibody production of B cells. Our results support the role of CD180 in the induction of natural autoantibody production, possibly by NS B cells, and suggest an imbalance between the pathologic and natural autoantibody production in SSc patients. Full article

(This article belongs to the Special Issue Immunophenotyping in Autoimmune Diseases and Cancer)

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27 pages, 3064 KiB

Open AccessArticle

Dysregulation of Placental Functions and Immune Pathways in Complete Hydatidiform Moles

by Jennifer R. King, Melissa L. Wilson, Szabolcs Hetey, Peter Kiraly, Koji Matsuo, Antonio V. Castaneda, Eszter Toth, Tibor Krenacs, Petronella Hupuczi, Paulette Mhawech-Fauceglia, Andrea Balogh, Andras Szilagyi, Janos Matko, Zoltan Papp, Lynda D. Roman, Victoria K. Cortessis and Nandor Gabor Than

Int. J. Mol. Sci. 2019, 20(20), 4999; https://doi.org/10.3390/ijms20204999 - 10 Oct 2019

Cited by 15 | Viewed by 6486

Abstract

Gene expression studies of molar pregnancy have been limited to a small number of candidate loci. We analyzed high-dimensional RNA and protein data to characterize molecular features of complete hydatidiform moles (CHMs) and corresponding pathologic pathways. CHMs and first trimester placentas were collected, histopathologically examined, then flash-frozen or paraffin-embedded. Frozen CHMs and control placentas were subjected to RNA-Seq, with resulting data and published placental RNA-Seq data subjected to bioinformatics analyses. Paraffin-embedded tissues from CHMs and control placentas were used for tissue microarray (TMA) construction, immunohistochemistry, and immunoscoring for galectin-14. Of the 14,022 protein-coding genes expressed in all samples, 3,729 were differentially expressed (DE) in CHMs, of which 72% were up-regulated. DE genes were enriched in placenta-specific genes (OR = 1.88, p = 0.0001), of which 79% were down-regulated, imprinted genes (OR = 2.38, p = 1.54 × 10⁻⁶), and immune genes (OR = 1.82, p = 7.34 × 10⁻¹⁸), of which 73% were up-regulated. DNA methylation-related enzymes and histone demethylases were dysregulated. “Cytokine–cytokine receptor interaction” was the most impacted of 38 dysregulated pathways, among which 17 were immune-related pathways. TMA-based immunoscoring validated the lower expression of galectin-14 in CHM. In conclusion, placental functions were down-regulated, imprinted gene expression was altered, and immune pathways were activated, indicating complex dysregulation of placental developmental and immune processes in CHMs. Full article

(This article belongs to the Special Issue Immunophenotyping in Autoimmune Diseases and Cancer)

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14 pages, 1465 KiB

Open AccessArticle

Altered Cell Surface N-Glycosylation of Resting and Activated T Cells in Systemic Lupus Erythematosus

by Enikő Szabó, Ákos Hornung, Éva Monostori, Márta Bocskai, Ágnes Czibula and László Kovács

Int. J. Mol. Sci. 2019, 20(18), 4455; https://doi.org/10.3390/ijms20184455 - 10 Sep 2019

Cited by 23 | Viewed by 3464

Abstract

Altered cell surface glycosylation in congenital and acquired diseases has been shown to affect cell differentiation and cellular responses to external signals. Hence, it may have an important role in immune regulation; however, T cell surface glycosylation has not been studied in systemic lupus erythematosus (SLE), a prototype of autoimmune diseases. Analysis of the glycosylation of T cells from patients suffering from SLE was performed by lectin-binding assay, flow cytometry, and quantitative real-time PCR. The results showed that resting SLE T cells presented an activated-like phenotype in terms of their glycosylation pattern. Additionally, activated SLE T cells bound significantly less galectin-1 (Gal-1), an important immunoregulatory lectin, while other lectins bound similarly to the controls. Differential lectin binding, specifically Gal-1, to SLE T cells was explained by the increased gene expression ratio of sialyltransferases and neuraminidase 1 (NEU1), particularly by elevated ST6 beta-galactosamide alpha-2,6-sialyltranferase 1 (ST6GAL1)/NEU1 and ST3 beta-galactoside alpha-2,3-sialyltransferase 6 (ST3GAL6)/NEU1 ratios. These findings indicated an increased terminal sialylation. Indeed, neuraminidase treatment of cells resulted in the increase of Gal-1 binding. Altered T cell surface glycosylation may predispose the cells to resistance to the immunoregulatory effects of Gal-1, and may thus contribute to the pathomechanism of SLE. Full article

(This article belongs to the Special Issue Immunophenotyping in Autoimmune Diseases and Cancer)

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13 pages, 3965 KiB

Open AccessArticle

Flow Cytometry Reveals the Nature of Oncotic Cells

by Anna Vossenkamper and Gary Warnes

Int. J. Mol. Sci. 2019, 20(18), 4379; https://doi.org/10.3390/ijms20184379 - 6 Sep 2019

Cited by 5 | Viewed by 6337

Abstract

The term necrosis is commonly applied to cells that have died via a non-specific pathway or mechanism but strictly is the description of the degradation processes involved once the plasma membrane of the cell has lost integrity. The signalling pathways potentially involved in accidental cell death (ACD) or oncosis are under-studied. In this study, the flow cytometric analysis of the intracellular antigens involved in regulated cell death (RCD) revealed the phenotypic nature of cells undergoing oncosis or necrosis. Sodium azide induced oncosis but also classic apoptosis, which was blocked by zVAD (z-Vla-Ala-Asp(OMe)-fluoromethylketone). Oncotic cells were found to be viability^+ve/caspase-3^–ve/RIP3^+ve/–ve (Receptor-interacting serine/threonine protein kinase 3). These two cell populations also displayed a DNA damage response (DDR) phenotype pH2AX^+ve/PARP^–ve, cleaved PARP induced caspase independent apoptosis H2AX^–ve/PARP^+ve and hyper-activation or parthanatos H2AX^+ve/PARP^+ve. Oncotic cells with phenotype cell viability^+ve/RIP3^–ve/caspase-3^–ve showed increased DDR and parthanatos. Necrostatin-1 down-regulated DDR in oncotic cells and increased sodium azide induced apoptosis. This flow cytometric approach to cell death research highlights the link between ACD and the RCD processes of programmed apoptosis and necrosis. Full article

(This article belongs to the Special Issue Immunophenotyping in Autoimmune Diseases and Cancer)

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Review

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21 pages, 1266 KiB

Open AccessReview

Endoplasmic Reticulum Stress Pathway, the Unfolded Protein Response, Modulates Immune Function in the Tumor Microenvironment to Impact Tumor Progression and Therapeutic Response

by Manuel U. Ramirez, Salvador R. Hernandez, David R. Soto-Pantoja and Katherine L. Cook

Int. J. Mol. Sci. 2020, 21(1), 169; https://doi.org/10.3390/ijms21010169 - 25 Dec 2019

Cited by 39 | Viewed by 6263

Abstract

Despite advances in cancer therapy, several persistent issues remain. These include cancer recurrence, effective targeting of aggressive or therapy-resistant cancers, and selective treatments for transformed cells. This review evaluates the current findings and highlights the potential of targeting the unfolded protein response to treat cancer. The unfolded protein response, an evolutionarily conserved pathway in all eukaryotes, is initiated in response to misfolded proteins accumulating within the lumen of the endoplasmic reticulum. This pathway is initially cytoprotective, allowing cells to survive stressful events; however, prolonged activation of the unfolded protein response also activates apoptotic responses. This balance is key in successful mammalian immune response and inducing cell death in malignant cells. We discuss how the unfolded protein response affects cancer progression, survival, and immune response to cancer cells. The literature shows that targeting the unfolded protein response as a monotherapy or in combination with chemotherapy or immunotherapies increases the efficacy of these drugs; however, systemic unfolded protein response targeting may yield deleterious effects on immune cell function and should be taken into consideration. The material in this review shows the promise of both approaches, each of which merits further research. Full article

(This article belongs to the Special Issue Immunophenotyping in Autoimmune Diseases and Cancer)

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22 pages, 2279 KiB

Open AccessReview

The Evolving Role of CD8⁺CD28⁻ Immunosenescent T Cells in Cancer Immunology

by Wei X. Huff, Jae Hyun Kwon, Mario Henriquez, Kaleigh Fetcko and Mahua Dey

Int. J. Mol. Sci. 2019, 20(11), 2810; https://doi.org/10.3390/ijms20112810 - 8 Jun 2019

Cited by 120 | Viewed by 23551

Abstract

Functional, tumor-specific CD8⁺ cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8⁺ effector T cell dysfunction. Among the many facets of CD8⁺ T cell dysfunction that have been recognized—tolerance, anergy, exhaustion, and senescence—CD8⁺ T cell senescence is incompletely understood. Naïve CD8⁺ T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8⁺CD28⁻ senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8⁺CD28⁻ senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8⁺ T cells could improve the efficacy of future anti-tumor immunotherapy. Full article

(This article belongs to the Special Issue Immunophenotyping in Autoimmune Diseases and Cancer)

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