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Article: Role of PARP Inhibitors in Cancer Immunotherapy: Potential Friends to Immune Activating Molecules and Foes to Immune Checkpoints.

Franzese, Ornella / Graziani, Grazia

2022 Volume 14, Issue 22

Abstract: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxic effects as single agents in tumors characterized by defective repair of DNA double-strand breaks deriving from BRCA1/2 mutations or other abnormalities in genes associated with ... ...

Abstract	Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxic effects as single agents in tumors characterized by defective repair of DNA double-strand breaks deriving from BRCA1/2 mutations or other abnormalities in genes associated with homologous recombination. Preclinical studies have shown that PARPi-induced DNA damage may affect the tumor immune microenvironment and immune-mediated anti-tumor response through several mechanisms. In particular, increased DNA damage has been shown to induce the activation of type I interferon pathway and up-regulation of PD-L1 expression in cancer cells, which can both enhance sensitivity to Immune Checkpoint Inhibitors (ICIs). Despite the recent approval of ICIs for a number of advanced cancer types based on their ability to reinvigorate T-cell-mediated antitumor immune responses, a consistent percentage of treated patients fail to respond, strongly encouraging the identification of combination therapies to overcome resistance. In the present review, we analyzed both established and unexplored mechanisms that may be elicited by PARPi, supporting immune reactivation and their potential synergism with currently used ICIs. This analysis may indicate novel and possibly patient-specific immune features that might represent new pharmacological targets of PARPi, potentially leading to the identification of predictive biomarkers of response to their combination with ICIs.
Language	English
Publishing date	2022-11-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14225633
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Article: Protein Kinase C at the Crossroad of Mutations, Cancer, Targeted Therapy and Immune Response.

Aquino, Angelo / Bianchi, Nicoletta / Terrazzan, Anna / Franzese, Ornella

Biology

2023 Volume 12, Issue 8

Abstract: The frequent PKC dysregulations observed in many tumors have made these enzymes natural targets for anticancer applications. Nevertheless, this considerable interest in the development of PKC modulators has not led to the expected therapeutic benefits, ... ...

Abstract	The frequent PKC dysregulations observed in many tumors have made these enzymes natural targets for anticancer applications. Nevertheless, this considerable interest in the development of PKC modulators has not led to the expected therapeutic benefits, likely due to the complex biological activities regulated by PKC isoenzymes, often playing ambiguous and protective functions, further driven by the occurrence of mutations. The structure, regulation and functions of PKCs have been extensively covered in other publications. Herein, we focused on PKC alterations mostly associated with complete functional loss. We also addressed the modest yet encouraging results obtained targeting PKC in selected malignancies and the more frequent negative clinical outcomes. The reported observations advocate the need for more selective molecules and a better understanding of the involved pathways. Furthermore, we underlined the most relevant immune mechanisms controlled by PKC isoforms potentially impacting the immune checkpoint inhibitor blockade-mediated immune recovery. We believe that a comprehensive examination of the molecular features of the tumor microenvironment might improve clinical outcomes by tailoring PKC modulation. This approach can be further supported by the identification of potential response biomarkers, which may indicate patients who may benefit from the manipulation of distinctive PKC isoforms.
Language	English
Publishing date	2023-07-26
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology12081047
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Article ; Online: Protein Kinase C at the Crossroad of Mutations, Cancer, Targeted Therapy and Immune Response

Aquino, Angelo / Bianchi, Nicoletta / Terrazzan, Anna / Franzese, Ornella

Biology (Basel). 2023 July 26, v. 12, no. 8

2023

Abstract	The frequent PKC dysregulations observed in many tumors have made these enzymes natural targets for anticancer applications. Nevertheless, this considerable interest in the development of PKC modulators has not led to the expected therapeutic benefits, likely due to the complex biological activities regulated by PKC isoenzymes, often playing ambiguous and protective functions, further driven by the occurrence of mutations. The structure, regulation and functions of PKCs have been extensively covered in other publications. Herein, we focused on PKC alterations mostly associated with complete functional loss. We also addressed the modest yet encouraging results obtained targeting PKC in selected malignancies and the more frequent negative clinical outcomes. The reported observations advocate the need for more selective molecules and a better understanding of the involved pathways. Furthermore, we underlined the most relevant immune mechanisms controlled by PKC isoforms potentially impacting the immune checkpoint inhibitor blockade-mediated immune recovery. We believe that a comprehensive examination of the molecular features of the tumor microenvironment might improve clinical outcomes by tailoring PKC modulation. This approach can be further supported by the identification of potential response biomarkers, which may indicate patients who may benefit from the manipulation of distinctive PKC isoforms.
Keywords	biomarkers ; immune response ; isozymes ; neoplasms ; protein kinase C ; therapeutics
Language	English
Dates of publication	2023-0726
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology12081047
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Article ; Online: T-cell repertoire diversity: friend or foe for protective antitumor response?

Porciello, Nicla / Franzese, Ornella / D'Ambrosio, Lorenzo / Palermo, Belinda / Nisticò, Paola

Journal of experimental & clinical cancer research : CR

2022 Volume 41, Issue 1, Page(s) 356

Abstract: Profiling the T-Cell Receptor (TCR) repertoire is establishing as a potent approach to investigate autologous and treatment-induced antitumor immune response. Technical and computational breakthroughs, including high throughput next-generation sequencing ...

Abstract	Profiling the T-Cell Receptor (TCR) repertoire is establishing as a potent approach to investigate autologous and treatment-induced antitumor immune response. Technical and computational breakthroughs, including high throughput next-generation sequencing (NGS) approaches and spatial transcriptomics, are providing unprecedented insight into the mechanisms underlying antitumor immunity. A precise spatiotemporal variation of T-cell repertoire, which dynamically mirrors the functional state of the evolving host-cancer interaction, allows the tracking of the T-cell populations at play, and may identify the key cells responsible for tumor eradication, the evaluation of minimal residual disease and the identification of biomarkers of response to immunotherapy. In this review we will discuss the relationship between global metrics characterizing the TCR repertoire such as T-cell clonality and diversity and the resultant functional responses. In particular, we will explore how specific TCR repertoires in cancer patients can be predictive of prognosis or response to therapy and in particular how a given TCR re-arrangement, following immunotherapy, can predict a specific clinical outcome. Finally, we will examine current improvements in terms of T-cell sequencing, discussing advantages and challenges of current methodologies.
Language	English
Publishing date	2022-12-22
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-022-02566-0
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Article ; Online: CD28/PD1 co-expression: dual impact on CD8

Palermo, Belinda / Franzese, Ornella / Frisullo, Giuseppe / D'Ambrosio, Lorenzo / Panetta, Mariangela / Campo, Giulia / D'Andrea, Daniel / Sperduti, Isabella / De Nicola, Francesca / Goeman, Frauke / Gallina, Filippo / Visca, Paolo / Facciolo, Francesco / Nisticò, Paola

Journal of experimental & clinical cancer research : CR

2023 Volume 42, Issue 1, Page(s) 287

Abstract: Background: Immune checkpoint blockade (ICB) has significantly prolonged survival of non-small cell lung cancer (NSCLC) patients, although most patients develop mechanisms of resistance. Recently single-cell RNA-sequencing (scRNA-Seq) revealed a huge T- ... ...

Abstract	Background: Immune checkpoint blockade (ICB) has significantly prolonged survival of non-small cell lung cancer (NSCLC) patients, although most patients develop mechanisms of resistance. Recently single-cell RNA-sequencing (scRNA-Seq) revealed a huge T-cell phenotypic and (dys)functional state variability. Accordingly, T-cell exhaustion is recognized as a functional adaptation, with a dynamic progression from a long-lived "pre-exhausted stem-like progenitor" to a "terminally exhausted" state. In this scenario it is crucial to understand the complex interplay between co-stimulatory and inhibitory molecules in CD8 Methods: To gain a baseline landscape of the composition, functional states, and transcriptomic signatures predictive of prognosis, we analyzed CD8 Results: Despite the increased PD1 levels, an improved PD1 Conclusions: Our findings identify signatures able to stratify survival of LUAD patients and predict ICB response in advanced NSCLC. CD28 is advocated as a key determinant in the signatures identified, in both periphery and tumor site, thus likely providing feasible biomarkers of ICB response.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/pathology ; CD8-Positive T-Lymphocytes ; CD28 Antigens/genetics ; CD28 Antigens/therapeutic use ; Immune Checkpoint Inhibitors/therapeutic use ; Hepatitis A Virus Cellular Receptor 2/genetics ; Lung Neoplasms/pathology ; Adenocarcinoma of Lung/pathology
Chemical Substances	CD28 Antigens ; Immune Checkpoint Inhibitors ; Hepatitis A Virus Cellular Receptor 2
Language	English
Publishing date	2023-10-28
Publishing country	England
Document type	Journal Article
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-023-02846-3
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Article ; Online: Distinct Hypericum perforatum L. total extracts exert different antitumour activity on erythroleukemic K562 cells.

Valletta, Elena / Rinaldi, Annamaria / Marini, Mario / Franzese, Ornella / Roscetti, Gianna

Phytotherapy research : PTR

2018 Volume 32, Issue 9, Page(s) 1803–1811

Abstract: Total flower extracts of Hypericum perforatum L. obtained with 3 different solvent systems were tested on tumour cell line cultures by comparing two groups of plants harvested in different times and places. The extracts, characterized according to the ... ...

Abstract	Total flower extracts of Hypericum perforatum L. obtained with 3 different solvent systems were tested on tumour cell line cultures by comparing two groups of plants harvested in different times and places. The extracts, characterized according to the spectroscopic profile and the hypericin content, were tested on the growth and apoptotic death of K562 cells, a human erythroleukemic cell line. Growth and apoptosis were analysed by viable cell count, flow cytometry, and fluorescence microscopy at 6, 24, and 48 hr of culture following 1 hr exposure to the extracts under investigation. Here, we show that Hypericum extracts are able to reduce the growth of K562 cells and induce different degrees and kinetics of apoptosis according to the group of plants of origin. Also, we highlighted interesting differences in terms of efficacy among the extracts, with some samples losing their effectiveness along the culture time and others able to maintain or even increase their efficacy. Furthermore, the data herein obtained confirm the role of non hypericin compounds that are present in different proportions in the two plant groups and in the extracts analysed.
MeSH term(s)	Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Flowers/chemistry ; Humans ; Hypericum/chemistry ; K562 Cells ; Perylene/analogs & derivatives ; Perylene/pharmacology ; Plant Extracts/pharmacology ; Solvents
Chemical Substances	Antineoplastic Agents, Phytogenic ; Plant Extracts ; Solvents ; Perylene (5QD5427UN7) ; hypericin (7V2F1075HD)
Language	English
Publishing date	2018-05-22
Publishing country	England
Document type	Journal Article
ZDB-ID	639136-9
ISSN	1099-1573 ; 0951-418X
ISSN (online)	1099-1573
ISSN	0951-418X
DOI	10.1002/ptr.6114
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Article ; Online: Beneficial and Detrimental Effects of Antiretroviral Therapy on HIV-Associated Immunosenescence.

Franzese, Ornella / Barbaccia, Maria Luisa / Bonmassar, Enzo / Graziani, Grazia

Chemotherapy

2018 Volume 63, Issue 2, Page(s) 64–75

Abstract: Since the introduction of highly active antiretroviral therapy more than 2 decades ago, HIV-related deaths have dramatically decreased and HIV infection has become a chronic disease. Due to the inability of antiretroviral drugs to eradicate the virus, ... ...

Abstract	Since the introduction of highly active antiretroviral therapy more than 2 decades ago, HIV-related deaths have dramatically decreased and HIV infection has become a chronic disease. Due to the inability of antiretroviral drugs to eradicate the virus, treatment of HIV infection requires a systemic lifelong therapy. However, even when successfully treated, HIV patients still show increased incidence of age-associated co-morbidities compared with uninfected individuals. Virus- induced immunosenescence, a process characterized by a progressive decline of immune system function, contributes to the premature ageing observed in HIV patients. Although antiretroviral therapy has significantly improved both the quality and length of patient lives, the life expectancy of treated patients is still shorter compared with that of uninfected individuals. In particular, while antiretroviral therapy can contrast some features of HIV-associated immunosenescence, several anti-HIV agents may themselves contribute to other aspects of immune ageing. Moreover, older HIV patients tend to have a worse immunological response to the antiviral therapy. In this review we will examine the available evidence on the role of antiretroviral therapy in the control of the main features regulating immunosenescence.
Language	English
Publishing date	2018-03-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	6708-8
ISSN	1421-9794 ; 0009-3157
ISSN (online)	1421-9794
ISSN	0009-3157
DOI	10.1159/000487534
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Article ; Online: hTERT Transduction Extends the Lifespan of Primary Pediatric Low-Grade Glioma Cells While Preserving the Biological Response to NGF.

Franzese, Ornella / Di Francesco, Angela M / Meco, Daniela / Graziani, Grazia / Cusano, Gabriella / Levati, Lauretta / Riccardi, Riccardo / Ruggiero, Antonio

Pathology oncology research : POR

2021 Volume 27, Page(s) 612375

Abstract: The neurotrophin nerve growth factor (NGF) modulates the growth of human gliomas and is able to induce cell differentiation through the engagement of tropomyosin receptor kinase A (TrkA) receptor, although the role played in controlling glioma survival ... ...

Abstract	The neurotrophin nerve growth factor (NGF) modulates the growth of human gliomas and is able to induce cell differentiation through the engagement of tropomyosin receptor kinase A (TrkA) receptor, although the role played in controlling glioma survival has proved controversial. Unfortunately, the slow growth rate of low-grade gliomas (LGG) has made it difficult to investigate NGF effects on these tumors in preclinical models. In fact, patient-derived low-grade human astrocytoma cells duplicate only a limited number of times in culture before undergoing senescence. Nevertheless, replicative senescence can be counteracted by overexpression of hTERT, the catalytic subunit of telomerase, which potentially increases the proliferative potential of human cells without inducing cancer-associated changes. We have extended, by hTERT transduction, the proliferative
MeSH term(s)	Brain Neoplasms ; Cell Culture Techniques/methods ; Glioma ; Humans ; Nerve Growth Factor/metabolism ; Telomerase/genetics ; Transduction, Genetic/methods ; Tumor Cells, Cultured
Chemical Substances	NGF protein, human ; Nerve Growth Factor (9061-61-4) ; Telomerase (EC 2.7.7.49)
Language	English
Publishing date	2021-04-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1375979-6
ISSN	1532-2807 ; 1219-4956
ISSN (online)	1532-2807
ISSN	1219-4956
DOI	10.3389/pore.2021.612375
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Article ; Online: Involvement of non-coding RNAs and transcription factors in the induction of Transglutaminase isoforms by ATRA.

Franzese, Ornella / Minotti, Linda / Aguiari, Gianluca / Corrà, Fabio / Cervellati, Carlo / Ferrari, Carlo / Volinia, Stefano / Bergamini, Carlo M / Bianchi, Nicoletta

Amino acids

2019 Volume 51, Issue 9, Page(s) 1273–1288

Abstract: The multifunctional protein Transglutaminase type 2, is associated with cancer epithelial mesenchymal transition, invasiveness, stemness and drugs resistance. Several variant isoforms and non-coding RNAs are present in cancer and this report explored the ...

Abstract	The multifunctional protein Transglutaminase type 2, is associated with cancer epithelial mesenchymal transition, invasiveness, stemness and drugs resistance. Several variant isoforms and non-coding RNAs are present in cancer and this report explored the expression of these transcripts of the TGM2 gene in cancer cell lines after induction with all-trans retinoic acid. The expression of truncated variants along with two long non-coding RNAs, was demonstrated. One of these is coded from the first intron and the Last Exon Variant is constituted by a sequence corresponding to the last three exons and the 3'UTR. Analysis of ChIP-seq data, from ENCODE project, highlighted factors interacting with intronic sequences, which could interfere with the progression of RNApol II at checkpoints, during the elongation process. Some relevant transcription factors, bound in an ATRA-dependent way, were found by RNA immunoprecipitation, notably GATA3 mainly enriched to Last Exon Variant non-coding RNA. The involvement of NMD in the regulation of the ratio among these transcripts was observed, as the prevalent recovering of Last Exon Variant to phUPF1-complexes, with decrease of the binding towards other selective targets. This study contributes to identify molecular mechanisms regulating the ratio among the variants and improves the knowledge about regulatory roles of the non-coding RNAs of the TGM2 gene.
MeSH term(s)	Chromatin Immunoprecipitation Sequencing ; GATA3 Transcription Factor/metabolism ; GTP-Binding Proteins/biosynthesis ; GTP-Binding Proteins/genetics ; HL-60 Cells ; Humans ; Isoenzymes/biosynthesis ; Isoenzymes/genetics ; Nonsense Mediated mRNA Decay ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; Transcription, Genetic ; Transglutaminases/biosynthesis ; Transglutaminases/genetics ; Tretinoin/pharmacology
Chemical Substances	GATA3 Transcription Factor ; Isoenzymes ; RNA, Long Noncoding ; Tretinoin (5688UTC01R) ; transglutaminase 2 (EC 2.3.2.-) ; Transglutaminases (EC 2.3.2.13) ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2019-08-22
Publishing country	Austria
Document type	Journal Article
ZDB-ID	1121341-3
ISSN	1438-2199 ; 0939-4451
ISSN (online)	1438-2199
ISSN	0939-4451
DOI	10.1007/s00726-019-02766-7
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Zs.A 3490: Show issues

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Article ; Online: Abscopal Effect and Drug-Induced Xenogenization: A Strategic Alliance in Cancer Treatment?

Franzese, Ornella / Torino, Francesco / Giannetti, Elisa / Cioccoloni, Giorgia / Aquino, Angelo / Faraoni, Isabella / Fuggetta, Maria Pia / De Vecchis, Liana / Giuliani, Anna / Kaina, Bernd / Bonmassar, Enzo

International journal of molecular sciences

2021 Volume 22, Issue 19

Abstract: The current state of cancer treatment is still far from being satisfactory considering the strong impairment of patients' quality of life and the high lethality of malignant diseases. Therefore, it is critical for innovative approaches to be tested in ... ...

Abstract	The current state of cancer treatment is still far from being satisfactory considering the strong impairment of patients' quality of life and the high lethality of malignant diseases. Therefore, it is critical for innovative approaches to be tested in the near future. In view of the crucial role that is played by tumor immunity, the present review provides essential information on the immune-mediated effects potentially generated by the interplay between ionizing radiation and cytotoxic antitumor agents when interacting with target malignant cells. Therefore, the radiation-dependent abscopal effect (i.e., a biological effect of ionizing radiation that occurs outside the irradiated field), the influence of cancer chemotherapy on the antigenic pattern of target neoplastic cells, and the immunogenic cell death (ICD) caused by anticancer agents are the main topics of this presentation. It is widely accepted that tumor immunity plays a fundamental role in generating an abscopal effect and that anticancer drugs can profoundly influence not only the host immune responses, but also the immunogenic pattern of malignant cells. Remarkably, several anticancer drugs impact both the abscopal effect and ICD. In addition, certain classes of anticancer agents are able to amplify already expressed tumor-associated antigens (TAA). More importantly, other drugs, especially triazenes, induce the appearance of new tumor neoantigens (TNA), a phenomenon that we termed drug-induced xenogenization (DIX). The adoption of the abscopal effect is proposed as a potential therapeutic modality when properly applied concomitantly with drug-induced increase in tumor cell immunogenicity and ICD. Although little to no preclinical or clinical studies are presently available on this subject, we discuss this issue in terms of potential mechanisms and therapeutic benefits. Upcoming investigations are aimed at evaluating how chemical anticancer drugs, radiation, and immunotherapies are interacting and cooperate in evoking the abscopal effect, tumor xenogenization and ICD, paving the way for new and possibly successful approaches in cancer therapy.
MeSH term(s)	Animals ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/therapeutic use ; Biomarkers ; Disease Management ; Disease Susceptibility ; Drug-Related Side Effects and Adverse Reactions/etiology ; Drug-Related Side Effects and Adverse Reactions/metabolism ; Humans ; Immunity/drug effects ; Immunity/radiation effects ; Models, Animal ; Neoplasms/complications ; Neoplasms/immunology ; Neoplasms/therapy ; Radiation Injuries/etiology ; Radiation Injuries/metabolism ; Radiation Injuries/pathology ; Radiation, Ionizing ; Radiotherapy/adverse effects ; Radiotherapy/methods
Chemical Substances	Antineoplastic Agents ; Biomarkers
Language	English
Publishing date	2021-10-01
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/ijms221910672
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