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Book ; Online: Novel Strategies for Anti-Tumor Vaccines

Accolla, Roberto S. / Bassani-Sternberg, Michal / Rammensee, Hans-Georg / Melief, Cornelis / Buonaguro, Luigi

2020

Keywords	Medicine ; Immunology ; Tumor vaccine ; HLA peptidome ; Tumor antigens ; neoantigens ; APC ; T helper cells (Th)
Size	1 electronic resource (170 pages)
Publisher	Frontiers Media SA
Document type	Book ; Online
Note	English ; Open Access
HBZ-ID	HT021230147
ISBN	9782889634880 ; 2889634884
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: The Road to HTLV-1-Induced Leukemia by Following the Subcellular Localization of HTLV-1-Encoded HBZ Protein.

Accolla, Roberto S

Frontiers in immunology

2022 Volume 13, Page(s) 940131

Abstract: Human T cell leukemia virus-1 (HTLV-1) is the causative agent of a severe cancer of the lymphoid lineage that develops in 3-5% of infected individuals after many years. HTLV-1 infection may also induce a serious inflammatory pathology of the nervous ... ...

Abstract	Human T cell leukemia virus-1 (HTLV-1) is the causative agent of a severe cancer of the lymphoid lineage that develops in 3-5% of infected individuals after many years. HTLV-1 infection may also induce a serious inflammatory pathology of the nervous system designated HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Two virus-encoded proteins, the viral transactivator Tax-1 and the HTLV-1 basic leucine-zipper factor HBZ, are strongly involved in the oncogenic process. Tax-1 is involved in initial phases of the oncogenic process. Conversely, HBZ seems to be involved in maintenance of the neoplastic state as witnessed by the generation of leukemic/lymphomatous phenotype in HBZ transgenic mice and the persistent expression of HBZ in all phases of the oncogenic process. Nevertheless, the intimate molecular and cellular mechanism mediated by the two viral proteins, particularly HBZ, in oncogenesis still remain elusive. An important step toward the complete comprehension of HBZ-associated oncogenicity is the clarification of the anatomical correlates of HBZ during the various phases of HTLV-1 infection to development of HTLV-1-associated inflammatory pathology and ultimately to the establishment of leukemia. In this review, I will summarize recent studies that have established for the first time a temporal and unidirectional expression of HBZ, beginning with an exclusive cytoplasmic localization in infected asymptomatic individuals and in HAM/TSP patients and ending to a progressive cytoplasmic-to-nuclear transition in leukemic cells. These results are framed within the present knowledge of HTLV-1 infection and the future lines of research that may shed new light on the complex mechanism of HTLV-1- mediated oncogenesis.
MeSH term(s)	Animals ; Basic-Leucine Zipper Transcription Factors/genetics ; Basic-Leucine Zipper Transcription Factors/metabolism ; Carcinogenesis ; Human T-lymphotropic virus 1/physiology ; Leukemia ; Mice ; Paraparesis, Tropical Spastic/genetics ; Retroviridae Proteins/genetics ; Retroviridae Proteins/metabolism ; Viral Proteins/genetics
Chemical Substances	Basic-Leucine Zipper Transcription Factors ; HBZ protein, human T-cell leukemia virus type I ; Retroviridae Proteins ; Viral Proteins
Language	English
Publishing date	2022-06-23
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.940131
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The NLR member CIITA: Master controller of adaptive and intrinsic immunity and unexpected tool in cancer immunotherapy.

Forlani, Greta / Shallak, Mariam / Gatta, Andrea / Shaik, Amruth K B / Accolla, Roberto S

Biomedical journal

2023 Volume 46, Issue 5, Page(s) 100631

Abstract: Human nucleotide-binding oligomerization domain (NOD)-like receptors (NLR) include a large family of proteins that have important functions in basic physio-pathological processes like inflammation, cell death and regulation of transcription of key ... ...

Abstract	Human nucleotide-binding oligomerization domain (NOD)-like receptors (NLR) include a large family of proteins that have important functions in basic physio-pathological processes like inflammation, cell death and regulation of transcription of key molecules for the homeostasis of the immune system. They are all characterized by a common backbone structure (the STAND ATPase module consisting in a nucleotide-binding domain (NBD), an helical domain 1 (HD1) and a winged helix domain (WHD), used by both prokaryotes and eukaryotes as defense mechanism. In this review, we will focus on the MHC class II transactivator (CIITA), the master regulator of MHC class II (MHC-II) gene expression and the founding member of NLR. Although a consistent part of the described NLR family components is often recalled as innate or intrinsic immune sensors, CIITA in fact occupies a special place as a unique example of regulator of both intrinsic and adaptive immunity. The description of the discovery of CIITA and the genetic and molecular characterization of its expression will be followed by the most recent studies that have unveiled this dual role of CIITA, key molecule in intrinsic immunity as restriction factor for human retroviruses and precious tool to induce the expression of MHC-II molecules in cancer cells, rendering them potent surrogate antigen presenting cells (APC) for their own tumor antigens.
MeSH term(s)	Humans ; Trans-Activators ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Immunotherapy ; Nucleotides ; Neoplasms/therapy
Chemical Substances	MHC class II transactivator protein ; Trans-Activators ; Nuclear Proteins ; Nucleotides
Language	English
Publishing date	2023-07-17
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2698541-X
ISSN	2320-2890 ; 2320-2890
ISSN (online)	2320-2890
ISSN	2320-2890
DOI	10.1016/j.bj.2023.100631
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Reply to the Letter to the Editor: "Importance of nasal secretions in the evaluation of mucosal immunity elicited by mRNA BNT162b2 COVID-19 vaccine" by Francavilla B et al.: Lack of a strong oral mucosal immune response: rethinking the route of COVID-19 vaccine boost administration?

Azzi, Lorenzo / Dalla Gasperina, Daniela / Accolla, Roberto Sergio / Forlani, Greta

EBioMedicine

2022 Volume 79, Page(s) 104005

MeSH term(s)	BNT162 Vaccine ; COVID-19/prevention & control ; COVID-19 Vaccines ; Humans ; Immunity, Mucosal ; RNA, Messenger
Chemical Substances	COVID-19 Vaccines ; RNA, Messenger ; BNT162 Vaccine (N38TVC63NU)
Language	English
Publishing date	2022-04-15
Publishing country	Netherlands
Document type	Letter ; Comment
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2022.104005
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: HTLV-1 Infection and Pathogenesis: New Insights from Cellular and Animal Models.

Forlani, Greta / Shallak, Mariam / Accolla, Roberto Sergio / Romanelli, Maria Grazia

International journal of molecular sciences

2021 Volume 22, Issue 15

Abstract: Since the discovery of the human T-cell leukemia virus-1 (HTLV-1), cellular and animal models have provided invaluable contributions in the knowledge of viral infection, transmission and progression of HTLV-associated diseases. HTLV-1 is the causative ... ...

Abstract	Since the discovery of the human T-cell leukemia virus-1 (HTLV-1), cellular and animal models have provided invaluable contributions in the knowledge of viral infection, transmission and progression of HTLV-associated diseases. HTLV-1 is the causative agent of the aggressive adult T-cell leukemia/lymphoma and inflammatory diseases such as the HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Cell models contribute to defining the role of HTLV proteins, as well as the mechanisms of cell-to-cell transmission of the virus. Otherwise, selected and engineered animal models are currently applied to recapitulate in vivo the HTLV-1 associated pathogenesis and to verify the effectiveness of viral therapy and host immune response. Here we review the current cell models for studying virus-host interaction, cellular restriction factors and cell pathway deregulation mediated by HTLV products. We recapitulate the most effective animal models applied to investigate the pathogenesis of HTLV-1-associated diseases such as transgenic and humanized mice, rabbit and monkey models. Finally, we summarize the studies on STLV and BLV, two closely related HTLV-1 viruses in animals. The most recent anticancer and HAM/TSP therapies are also discussed in view of the most reliable experimental models that may accelerate the translation from the experimental findings to effective therapies in infected patients.
MeSH term(s)	Animals ; Disease Models, Animal ; HTLV-I Infections/metabolism ; HTLV-I Infections/pathology ; HTLV-I Infections/therapy ; Human T-lymphotropic virus 1/metabolism ; Human T-lymphotropic virus 1/pathogenicity ; Humans ; Leukemia-Lymphoma, Adult T-Cell/metabolism ; Leukemia-Lymphoma, Adult T-Cell/pathology ; Leukemia-Lymphoma, Adult T-Cell/therapy ; Mice ; Mice, Transgenic
Language	English
Publishing date	2021-07-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22158001
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Tripartite Motif 22 and Class II Transactivator Restriction Factors: Unveiling Their Concerted Action against Retroviruses.

Forlani, Greta / Accolla, Roberto S

Frontiers in immunology

2017 Volume 8, Page(s) 1362

Abstract: Coevolution of the three basic mechanisms of immunity, intrinsic, innate and adaptive, is a constant feature of the host defense against pathogens. Within this frame, a peculiar role is played by restriction factors (RFs), elements of intrinsic immunity ... ...

Abstract	Coevolution of the three basic mechanisms of immunity, intrinsic, innate and adaptive, is a constant feature of the host defense against pathogens. Within this frame, a peculiar role is played by restriction factors (RFs), elements of intrinsic immunity that interfere with viral life cycle. Often considered as molecules whose specific functions are distinct and unrelated among themselves recent results indicate instead, at least for some of them, a concerted action against the pathogen. Here we review recent findings on the antiviral activity of tripartite motif 22 (TRIM22) and class II transactivator (CIITA), first discovered as human immunodeficiency virus 1 RFs, but endowed with general antiviral activity. TRIM22 and CIITA provide the first example of cellular proteins acting together to potentiate their intrinsic immunity.
Language	English
Publishing date	2017
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2017.01362
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Protective anti-tumor vaccination against glioblastoma expressing the MHC class II transactivator CIITA.

Celesti, Fabrizio / Gatta, Andrea / Shallak, Mariam / Chiaravalli, Anna Maria / Cerati, Michele / Sessa, Fausto / Accolla, Roberto S / Forlani, Greta

Frontiers in immunology

2023 Volume 14, Page(s) 1133177

Abstract: Glioblastoma is the most malignant tumor of the central nervous system. Current treatments based on surgery, chemotherapy, and radiotherapy, and more recently on selected immunological approaches, unfortunately produce dismal outcomes, and less than 2% ... ...

Abstract	Glioblastoma is the most malignant tumor of the central nervous system. Current treatments based on surgery, chemotherapy, and radiotherapy, and more recently on selected immunological approaches, unfortunately produce dismal outcomes, and less than 2% of patients survive after 5 years. Thus, there is an urgent need for new therapeutic strategies. Here, we report unprecedented positive results in terms of protection from glioblastoma growth in an animal experimental system after vaccination with glioblastoma GL261 cells stably expressing the MHC class II transactivator CIITA. Mice injected with GL261-CIITA express
MeSH term(s)	Animals ; Mice ; CD4-Positive T-Lymphocytes ; Histocompatibility Antigens Class II ; Trans-Activators/genetics ; Glioblastoma/therapy ; Glioblastoma/metabolism
Chemical Substances	MHC class II transactivator protein ; Histocompatibility Antigens Class II ; Trans-Activators
Language	English
Publishing date	2023-03-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1133177
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Unveiling the Hidden Treasury: CIITA-Driven MHC Class II Expression in Tumor Cells to Dig up the Relevant Repertoire of Tumor Antigens for Optimal Stimulation of Tumor Specific CD4+ T Helper Cells.

Forlani, Greta / Shallak, Mariam / Celesti, Fabrizio / Accolla, Roberto S

Cancers

2020 Volume 12, Issue 11

Abstract: Despite the recent enthusiasm generated by novel immunotherapeutic approaches against cancer based on immune checkpoint inhibitors, it becomes increasingly clear that single immune-based strategies are not sufficient to defeat the various forms and types ...

Abstract	Despite the recent enthusiasm generated by novel immunotherapeutic approaches against cancer based on immune checkpoint inhibitors, it becomes increasingly clear that single immune-based strategies are not sufficient to defeat the various forms and types of tumors. Within this frame, novel vaccination strategies that are based on optimal stimulation of the key cell governing adaptive immunity, the CD4+ T helper cell, will certainly help in constructing more efficient treatments. In this review, we will focus on this aspect, mainly describing our past and recent contributions that, starting with a rather unorthodox approach, have ended up with the proposition of a new idea for making available an unprecedented extended repertoire of tumor antigens, both in quantitative and qualitative terms, to tumor-specific CD4+ T helper cells. Our approach is based on rendering the very same tumor cells antigen presenting cells for their own tumor antigens by gene transfer of CIITA, the major transcriptional coordinator of MHC class II expression discovered in our laboratory. CIITA-driven MHC class II-expressing tumor cells optimally stimulate in vivo tumor specific MHC class II-restricted CD4 T cells generating specific and long lasting protective immunity against the tumor. We will discuss the mechanism underlying protection and elaborate not only on the applicability of this approach for novel vaccination strategies amenable to clinical setting, but also on the consequence of our discoveries on sedimented immunological dogmas that are related to antigen presentation.
Language	English
Publishing date	2020-10-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12113181
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The endogenous HBZ interactome in ATL leukemic cells reveals an unprecedented complexity of host interacting partners involved in RNA splicing.

Shallak, Mariam / Alberio, Tiziana / Fasano, Mauro / Monti, Maria / Iacobucci, Ilaria / Ladet, Julien / Mortreux, Franck / Accolla, Roberto S / Forlani, Greta

Frontiers in immunology

2022 Volume 13, Page(s) 939863

Abstract: Adult T-cell leukemia/lymphoma (ATL) is a T-cell lymphoproliferative neoplasm caused by the human T-cell leukemia virus type 1 (HTLV-1). Two viral proteins, Tax-1 and HBZ play important roles in HTLV-1 infectivity and in HTLV-1-associated pathologies by ... ...

Abstract	Adult T-cell leukemia/lymphoma (ATL) is a T-cell lymphoproliferative neoplasm caused by the human T-cell leukemia virus type 1 (HTLV-1). Two viral proteins, Tax-1 and HBZ play important roles in HTLV-1 infectivity and in HTLV-1-associated pathologies by altering key pathways of cell homeostasis. However, the molecular mechanisms through which the two viral proteins, particularly HBZ, induce and/or sustain the oncogenic process are still largely elusive. Previous results suggested that HBZ interaction with nuclear factors may alter cell cycle and cell proliferation. To have a more complete picture of the HBZ interactions, we investigated in detail the endogenous HBZ interactome in leukemic cells by immunoprecipitating the HBZ-interacting complexes of ATL-2 leukemic cells, followed by tandem mass spectrometry analyses. RNA seq analysis was performed to decipher the differential gene expression and splicing modifications related to HTLV-1. Here we compared ATL-2 with MOLT-4, a non HTLV-1 derived leukemic T cell line and further compared with HBZ-induced modifications in an isogenic system composed by Jurkat T cells and stably HBZ transfected Jurkat derivatives. The endogenous HBZ interactome of ATL-2 cells identified 249 interactors covering three main clusters corresponding to protein families mainly involved in mRNA splicing, nonsense-mediated RNA decay (NMD) and JAK-STAT signaling pathway. Here we analyzed in detail the cluster involved in RNA splicing. RNAseq analysis showed that HBZ specifically altered the transcription of many genes, including crucial oncogenes, by affecting different splicing events. Consistently, the two RNA helicases, members of the RNA splicing family, DDX5 and its paralog DDX17, recently shown to be involved in alternative splicing of cellular genes after NF-κB activation by HTLV-1 Tax-1, interacted and partially co-localized with HBZ. For the first time, a complete picture of the endogenous HBZ interactome was elucidated. The wide interaction of HBZ with molecules involved in RNA splicing and the subsequent transcriptome alteration strongly suggests an unprecedented complex role of the viral oncogene in the establishment of the leukemic state.
MeSH term(s)	Adult ; Alternative Splicing ; Basic-Leucine Zipper Transcription Factors/metabolism ; DEAD-box RNA Helicases/metabolism ; Human T-lymphotropic virus 1/physiology ; Humans ; RNA Splicing ; Retroviridae Proteins/metabolism ; Viral Proteins/metabolism
Chemical Substances	Basic-Leucine Zipper Transcription Factors ; HBZ protein, human T-cell leukemia virus type I ; Retroviridae Proteins ; Viral Proteins ; Ddx5 protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2022-08-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.939863
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: CIITA-Driven MHC Class II Expressing Tumor Cells as Antigen Presenting Cell Performers: Toward the Construction of an Optimal Anti-tumor Vaccine.

Accolla, Roberto S / Ramia, Elise / Tedeschi, Alessandra / Forlani, Greta

Frontiers in immunology

2019 Volume 10, Page(s) 1806

Abstract: Construction of an optimal vaccine against tumors relies on the availability of appropriate tumor-specific antigens capable to stimulate CD4+ T helper cells (TH) and CD8+ cytolytic T cells (CTL). CTL are considered the major effectors of the anti-tumor ... ...

Abstract	Construction of an optimal vaccine against tumors relies on the availability of appropriate tumor-specific antigens capable to stimulate CD4+ T helper cells (TH) and CD8+ cytolytic T cells (CTL). CTL are considered the major effectors of the anti-tumor adaptive immune response as they recognize antigens presented on MHC class I (MHC-I) molecules usually expressed in all cells and thus also in tumors. However, attempts to translate in clinics vaccination protocols based only on tumor-specific MHC-I-bound peptides have resulted in very limited, if any, success. We believe failure was mostly due to inadequate triggering of the TH arm of adaptive immunity, as TH cells are necessary to trigger and maintain the proliferation of all the immune effector cells required to eliminate tumor cells. In this review, we focus on a novel strategy of anti-tumor vaccination established in our laboratory and based on the persistent expression of MHC class II (MHC-II) molecules in tumor cells. MHC-II are the restricting elements of TH recognition. They are usually not expressed in solid tumors. By genetically modifying tumor cells of distinct histological origin with the MHC-II transactivator CIITA, the physiological controller of MHC-II gene expression discovered in our laboratory, stable expression of all MHC class II genes was obtained. This resulted in tumor rejection or strong retardation of tumor growth
MeSH term(s)	Animals ; Antigen-Presenting Cells/immunology ; Antigen-Presenting Cells/pathology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/pathology ; Cancer Vaccines/genetics ; Cancer Vaccines/immunology ; Cancer Vaccines/therapeutic use ; Gene Expression Regulation, Neoplastic/immunology ; Histocompatibility Antigens Class II/genetics ; Histocompatibility Antigens Class II/immunology ; Humans ; Neoplasm Proteins/genetics ; Neoplasm Proteins/immunology ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Nuclear Proteins/genetics ; Nuclear Proteins/immunology ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/pathology ; Trans-Activators/genetics ; Trans-Activators/immunology
Chemical Substances	Cancer Vaccines ; Histocompatibility Antigens Class II ; MHC class II transactivator protein ; Neoplasm Proteins ; Nuclear Proteins ; Trans-Activators
Language	English
Publishing date	2019-07-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.01806
Database	MEDical Literature Analysis and Retrieval System OnLINE

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