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1.
Cancer Immunol Res ; 5(1): 29-41, 2017 01.
Article in English | MEDLINE | ID: mdl-27923825

ABSTRACT

Murine syngeneic tumor models are critical to novel immuno-based therapy development, but the molecular and immunologic features of these models are still not clearly defined. The translational relevance of differences between the models is not fully understood, impeding appropriate preclinical model selection for target validation, and ultimately hindering drug development. Across a panel of commonly used murine syngeneic tumor models, we showed variable responsiveness to immunotherapies. We used array comparative genomic hybridization, whole-exome sequencing, exon microarray analysis, and flow cytometry to extensively characterize these models, which revealed striking differences that may underlie these contrasting response profiles. We identified strong differential gene expression in immune-related pathways and changes in immune cell-specific genes that suggested differences in tumor immune infiltrates between models. Further investigation using flow cytometry showed differences in both the composition and magnitude of the tumor immune infiltrates, identifying models that harbor "inflamed" and "non-inflamed" tumor immune infiltrate phenotypes. We also found that immunosuppressive cell types predominated in syngeneic mouse tumor models that did not respond to immune-checkpoint blockade, whereas cytotoxic effector immune cells were enriched in responsive models. A cytotoxic cell-rich tumor immune infiltrate has been correlated with increased efficacy of immunotherapies in the clinic, and these differences could underlie the varying response profiles to immunotherapy between the syngeneic models. This characterization highlighted the importance of extensive profiling and will enable investigators to select appropriate models to interrogate the activity of immunotherapies as well as combinations with targeted therapies in vivo Cancer Immunol Res; 5(1); 29-41. ©2016 AACR.


Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Drug Discovery , Drug Evaluation, Preclinical , Animals , B7-H1 Antigen/antagonists & inhibitors , CTLA-4 Antigen/antagonists & inhibitors , Comparative Genomic Hybridization , DNA Copy Number Variations , Disease Models, Animal , Drug Synergism , Exome , Gene Expression Regulation, Neoplastic/drug effects , Genomics/methods , High-Throughput Nucleotide Sequencing , Immunomodulation/drug effects , Immunomodulation/genetics , Mice , Molecular Targeted Therapy , Mutation , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/metabolism , Signal Transduction/drug effects , Transcriptome , Tumor Microenvironment/drug effects , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
2.
Stem Cells Dev ; 22(22): 2990-3002, 2013 Nov 15.
Article in English | MEDLINE | ID: mdl-23819720

ABSTRACT

Allogeneic stem cell (SC)-based therapy is a promising tool for the treatment of a range of human degenerative and inflammatory diseases. Many reports highlighted the immune modulatory properties of some SC types, such as mesenchymal stromal cells (MSCs), but a comparative study with SCs of different origin, to assess whether immune regulation is a general SC property, is still lacking. To this aim, we applied highly standardized methods employed for MSC characterization to compare the immunological properties of bone marrow-MSCs, olfactory ectomesenchymal SCs, leptomeningeal SCs, and three different c-Kit-positive SC types, that is, amniotic fluid SCs, cardiac SCs, and lung SCs. We found that all the analyzed human SCs share a common pattern of immunological features, in terms of expression of activation markers ICAM-1, VCAM-1, HLA-ABC, and HLA-DR, modulatory activity toward purified T, B, and NK cells, lower immunogenicity of inflammatory-primed SCs as compared to resting SCs, and indoleamine-2,3-dioxygenase-activation as molecular inhibitory pathways, with some SC type-related peculiarities. Moreover, the SC types analyzed exert an anti-apoptotic effect toward not-activated immune effector cells (IECs). In addition, we found that the inhibitory behavior is not a constitutive property of SCs, but is acquired as a consequence of IEC activation, as previously described for MSCs. Thus, immune regulation is a general property of SCs and the characterization of this phenomenon may be useful for a proper therapeutic use of SCs.


Subject(s)
Amniotic Fluid/cytology , Bone Marrow Cells/cytology , Lung/cytology , Meninges/cytology , Mesenchymal Stem Cells/cytology , Myocardium/cytology , Olfactory Bulb/cytology , Amniotic Fluid/immunology , Antigens, CD/genetics , Antigens, CD/immunology , Biomarkers/metabolism , Bone Marrow Cells/immunology , Gene Expression , HLA Antigens/genetics , HLA Antigens/immunology , Humans , Immunophenotyping , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/immunology , Lung/immunology , Lymphocyte Subsets/cytology , Lymphocyte Subsets/immunology , Meninges/immunology , Mesenchymal Stem Cells/immunology , Myocardium/immunology , Olfactory Bulb/immunology , Organ Specificity , Primary Cell Culture , Vascular Cell Adhesion Molecule-1/genetics , Vascular Cell Adhesion Molecule-1/immunology
3.
PLoS One ; 8(4): e60136, 2013.
Article in English | MEDLINE | ID: mdl-23565196

ABSTRACT

Death receptor (DR3) 3 is a member of the TNFR superfamily. Its ligand is TNF-like ligand 1A (TL1A), a member of the TNF superfamily. TL1A/DR3 interactions have been reported to modulate the functions of T cells, NK, and NKT cells and play a crucial role in driving inflammatory processes in several T-cell-dependent autoimmune diseases. However, TL1A expression and effects on B cells remain largely unknown. In this study, we described for the first time that B cells from human blood express significant amounts of DR3 in response to B cell receptor polyclonal stimulation. The relevance of these results has been confirmed by immunofluorescence analysis in tonsil and spleen tissue specimens, which showed the in situ expression of DR3 in antigen-stimulated B cells in vivo. Remarkably, we demonstrated that TL1A reduces B-cell proliferation induced by anti-IgM-antibodies and IL-2 but did not affect B-cell survival, suggesting that TL1A inhibits the signal(s) important for B-cell proliferation. These results revealed a novel function of TL1A in modulating B-cell proliferation in vitro and suggest that TL1A may contribute to homeostasis of effector B-cell functions in immune response and host defense, thus supporting the role of the TL1A/DR3 functional axis in modulating the adaptive immune response.


Subject(s)
B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Tumor Necrosis Factor Ligand Superfamily Member 15/pharmacology , Antigens, CD/metabolism , B-Lymphocytes/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Immunophenotyping , Palatine Tonsil/immunology , Palatine Tonsil/metabolism , Receptors, Tumor Necrosis Factor, Member 25/metabolism
4.
Stem Cells Dev ; 22(12): 1789-801, 2013 Jun 15.
Article in English | MEDLINE | ID: mdl-23339531

ABSTRACT

Clinical-grade mesenchymal stromal cells (MSCs) are usually expanded from bone marrow (BMMSCs) or adipose tissue (ADSCs) using processes mainly differing in the use of fetal calf serum (FCS) or human platelet lysate (PL). We aimed to compare immune modulatory properties of clinical-grade MSCs using a combination of fully standardized in vitro assays. BMMSCs expanded with FCS (BMMSC-FCS) or PL (BMMSC-PL), and ADSC-PL were analyzed in quantitative phenotypic and functional experiments, including their capacity to inhibit the proliferation of T, B, and NK cells. The molecular mechanisms supporting T-cell inhibition were investigated. These parameters were also evaluated after pre-stimulation of MSCs with inflammatory cytokines. BMMSC-FCS, BMMSC-PL, and ADSC-PL displayed significant differences in expression of immunosuppressive and adhesion molecules. Standardized functional assays revealed that resting MSCs inhibited proliferation of T and NK cells, but not B cells. ADSC-PL were the most potent in inhibiting T-cell growth, a property ascribed to interferon-γ-dependent indoleamine 2,3-dioxygenase activity. MSCs did not stimulate allogeneic T cell proliferation but were efficiently lysed by activated NK cells. The systematic use of quantitative and reproducible validation techniques highlights differences in immunological properties of MSCs produced using various clinical-grade processes. ADSC-PL emerge as a promising candidate for future clinical trials.


Subject(s)
Adipose Tissue/cytology , Bone Marrow Cells/cytology , Mesenchymal Stem Cells/cytology , Adipose Tissue/drug effects , Adipose Tissue/immunology , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Blood Platelets/chemistry , Blood Platelets/immunology , Bone Marrow Cells/drug effects , Bone Marrow Cells/immunology , Cattle , Cell Extracts/chemistry , Cell Extracts/pharmacology , Cell Proliferation , Coculture Techniques , Cytokines/biosynthesis , Cytokines/immunology , Humans , Immunomodulation , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/immunology , Organ Specificity , Quality Control , Serum/chemistry , Serum/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology
5.
Transfus Apher Sci ; 47(2): 193-8, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22818214

ABSTRACT

Adipose-derived stromal cells (ASCs) are now emerging as a good alternative to bone marrow derived mesenchymal stromal cells (BM-MSC) for cellular therapy. Similarly to BM-MSC, ASCs can be easily isolated as adherent fibroblastoid cell population after processing lipoaspirate samples. Lipoaspiration provides a great number of cells, without extensive manipulation. ASCs express classical mesenchymal markers and only at early passages express CD34. ASCs can differentiate in cells of mesodermal lineages, such as adipocytes, osteocytes and condrocytes. ASCs share with BM-MSC the same ability to inhibit the proliferation of allogeneic, activated immune cells, thus affecting in vivo in animal models the onset and course of rheumatoid arthritis (RA), experimental autoimmune encephalomyelitis (EAE), Crohn's disease (CD), ulcerous colitis (UC) and graft-versus-host disease (GvHD). On the other hand, the main molecular pathway involved in this effect is still unclear. On the basis of this functional property, ASCs are used in different clinical trials to treat RA, CD, UC and GvHD. However, the most promising field of clinical application is represented by bone defect repair. Despite the ability to regenerate injured tissues and to block the progression of inflammatory disorders, some authors reported that ASCs can also induce, in in vivo animal models, the growth and vascularization of solid and hematological tumors. Conversely, ASCs have been shown to hamper tumor cell proliferation, reduce cell viability and induce necrosis. Thus, more accurate studies, collaborative protocols, high standardization of methods, and safety controls are required to exclude transformation of transplanted ASCs.


Subject(s)
Adipocytes/cytology , Stromal Cells/cytology , Animals , Cell Differentiation/physiology , Cell Growth Processes/physiology , Humans , Immunophenotyping , Models, Animal
6.
PLoS One ; 7(5): e35639, 2012.
Article in English | MEDLINE | ID: mdl-22567106

ABSTRACT

Mesenchymal stromal cells (MSCs) reside in many organs including lung, as shown by their isolation from fetal lung tissues, bronchial stromal compartment, bronchial-alveolar lavage and transplanted lung tissues. It is still controversial whether lung MSCs can undergo mesenchymal-to-epithelial-transition (MET) and possess immune regulatory properties. To this aim, we isolated, expanded and characterized MSCs from normal adult human lung (lung-hMSCs) and compared with human bone marrow-derived MSCs (BM-hMSCs). Our results show that lung-MSCs reside at the perivascular level and do not significantly differ from BM-hMSCs in terms of immunophenotype, stemness gene profile, mesodermal differentiation potential and modulation of T, B and NK cells. However, lung-hMSCs express higher basal level of the stemness-related marker nestin and show, following in vitro treatment with retinoic acid, higher epithelial cell polarization, which is anyway partial when compared to a control epithelial bronchial cell line. Although these results question the real capability of acquiring epithelial functions by MSCs and the feasibility of MSC-based therapeutic approaches to regenerate damaged lung tissues, the characterization of this lung-hMSC population may be useful to study the involvement of stromal cell compartment in lung diseases in which MET plays a role, such as in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.


Subject(s)
Bone Marrow Cells/cytology , Lung/cytology , Mesenchymal Stem Cells/cytology , Cell Differentiation/physiology , Cells, Cultured , Epithelial-Mesenchymal Transition/physiology , Humans , Immunophenotyping , Reverse Transcriptase Polymerase Chain Reaction
7.
World J Stem Cells ; 2(3): 50-60, 2010 Jun 26.
Article in English | MEDLINE | ID: mdl-21607122

ABSTRACT

The possibility of treating degenerative diseases by stem cell-based approaches is a promising therapeutical option. Among major concerns for the clinical application of stem cells, some derive from the possibility that stem cells may be rejected by the immune system as a consequence of histoincompatibility and that stem cells themselves may interfere with the normal functions of host immune response. Therefore, the immunogenicity and the immunomodulatory properties of stem cells must be carefully addressed. Although these properties are common features of different stem cell types, some peculiarities can be recognized and characterized for their proper clinical use.

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