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Article ; Online: The Multifaceted Role of Human Dickkopf-3 (DKK-3) in Development, Immune Modulation and Cancer.

Mourtada, Jana / Thibaudeau, Chloé / Wasylyk, Bohdan / Jung, Alain C

2023 Volume 13, Issue 1

Abstract: The human Dickkopf (DKK) family includes four main secreted proteins, DKK-1, DKK-2, DKK-3, and DKK-4, as well as the DKK-3 related protein soggy (Sgy-1 or DKKL1). These glycoproteins play crucial roles in various biological processes, and especially ... ...

Abstract	The human Dickkopf (DKK) family includes four main secreted proteins, DKK-1, DKK-2, DKK-3, and DKK-4, as well as the DKK-3 related protein soggy (Sgy-1 or DKKL1). These glycoproteins play crucial roles in various biological processes, and especially modulation of the Wnt signaling pathway. DKK-3 is distinct, with its multifaceted roles in development, stem cell differentiation and tissue homeostasis. Intriguingly, DKK-3 appears to have immunomodulatory functions and a complex role in cancer, acting as either a tumor suppressor or an oncogene, depending on the context. DKK-3 is a promising diagnostic and therapeutic target that can be modulated by epigenetic reactivation, gene therapy and DKK-3-blocking agents. However, further research is needed to optimize DKK-3-based therapies. In this review, we comprehensively describe the known functions of DKK-3 and highlight the importance of context in understanding and exploiting its roles in health and disease.
MeSH term(s)	Humans ; Cell Differentiation ; Epigenomics ; Genetic Therapy ; Intercellular Signaling Peptides and Proteins ; Neoplasms/genetics ; Oncogenes
Chemical Substances	DKKL1 protein, human ; Intercellular Signaling Peptides and Proteins ; DKK3 protein, human
Language	English
Publishing date	2023-12-29
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells13010075
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Article: Immunotherapy Breakthroughs in the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

Borel, Christian / Jung, Alain C / Burgy, Mickaël

Cancers

2020 Volume 12, Issue 9

Abstract: Head and neck squamous cell carcinoma (HNSCC) in the recurrent or metastatic (R/M) setting is a devastating disease with a poor prognosis. Until recently, the reference first line treatment was the EXTREME protocol, which yields a 10.1 months median ... ...

Abstract	Head and neck squamous cell carcinoma (HNSCC) in the recurrent or metastatic (R/M) setting is a devastating disease with a poor prognosis. Until recently, the reference first line treatment was the EXTREME protocol, which yields a 10.1 months median survival, and almost no effective treatment are available in second line. Immune checkpoint inhibitors (ICIs) have changed the prognosis of several metastatic solid tumors. Given their inflammatory profile and high mutational burden, HNSCC is a good candidate for ICIs treatments. First, a strong pembrolizumab efficacy signal was shown in the Keynote-012 Phase Ib study. Then, the phase III Checkmate-141 study validated the efficacy of nivolumab in platinum-resistant patients. Finally, the first line conquest is acquired since the final results of the keynote-048 phase III study that demonstrated the superiority of pembrolizumab versus EXTREME in CPS ≥ 1 patients, and with the addition of platinum and 5FU in all patients. However, the first line treatment landscape is not frozen. Two studies (Checkmate-651 and Kestrel) are investigating the efficacy of the combination of antibodies raised against CTLA-4 and PD-(L)1. Results are impatiently awaited. Further progress needs the use of new immunotherapeutic agents such as monalizumab or ICOS agonist rather in combination with an anti-PD(L)1. New associations of ICIs and chemotherapeutic or targeted therapeutic agents are also actively investigated. Finally, ICIs has to be studied in the locally advanced setting where there is a chance of cure. Several trials are testing the potential synergistic combination of ICIs with radiotherapy and platinum or cetuximab, or ICIs used in a neoadjuvant setting.
Language	English
Publishing date	2020-09-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12092691
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Article ; Online: A Novel Near-IR Absorbing Ruthenium(II) Complex as Photosensitizer for Photodynamic Therapy and its Cetuximab Bioconjugates.

Martínez-Alonso, Marta / Gandioso, Albert / Thibaudeau, Chloé / Qin, Xue / Arnoux, Philippe / Demeubayeva, Nurikamal / Guérineau, Vincent / Frochot, Céline / Jung, Alain C / Gaiddon, Christian / Gasser, Gilles

Chembiochem : a European journal of chemical biology

2023 Volume 24, Issue 15, Page(s) e202300203

Abstract: A novel Ru(II) cyclometalated photosensitizer (PS), Ru- ... ...

Abstract	A novel Ru(II) cyclometalated photosensitizer (PS), Ru-NH
MeSH term(s)	Photosensitizing Agents/pharmacology ; Photosensitizing Agents/chemistry ; Cetuximab/pharmacology ; Ruthenium/chemistry ; Coordination Complexes/chemistry ; Photochemotherapy
Chemical Substances	Photosensitizing Agents ; Cetuximab (PQX0D8J21J) ; Ruthenium (7UI0TKC3U5) ; Coordination Complexes
Language	English
Publishing date	2023-07-05
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020469-3
ISSN	1439-7633 ; 1439-4227
ISSN (online)	1439-7633
ISSN	1439-4227
DOI	10.1002/cbic.202300203
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Article ; Online: Can liberating p53 from E6 free patients from HPV-related head and neck tumors?

Jung, Alain C

Cell cycle (Georgetown, Tex.)

2013 Volume 12, Issue 6, Page(s) 868

MeSH term(s)	Carcinoma, Squamous Cell/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Head and Neck Neoplasms/metabolism ; Humans ; Oncogene Proteins, Viral/genetics ; Papillomavirus E7 Proteins/genetics ; Repressor Proteins/genetics ; Squamous Cell Carcinoma of Head and Neck ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Cyclin-Dependent Kinase Inhibitor p21 ; E6 protein, Human papillomavirus type 16 ; Oncogene Proteins, Viral ; Papillomavirus E7 Proteins ; Repressor Proteins ; Tumor Suppressor Protein p53 ; oncogene protein E7, Human papillomavirus type 16
Language	English
Publishing date	2013-02-26
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.24101
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Article: Antitumor Immune Response Triggered by Metal-Based Photosensitizers for Photodynamic Therapy: Where Are We?

Jung, Alain C / Moinard-Butot, Fabien / Thibaudeau, Chloé / Gasser, Gilles / Gaiddon, Christian

Pharmaceutics

2021 Volume 13, Issue 11

Abstract: Metal complexes based on transition metals have rich photochemical and photophysical properties that are derived from a variety of excited state electronic configurations triggered by visible and near-infrared light. These properties can be exploited to ... ...

Abstract	Metal complexes based on transition metals have rich photochemical and photophysical properties that are derived from a variety of excited state electronic configurations triggered by visible and near-infrared light. These properties can be exploited to produce powerful energy and electron transfer processes that can lead to oxygen-(in)dependent photobiological activity. These principles are the basis of photodynamic therapy (PDT), which is a clinically approved treatment that offers a promising, effective, and noninvasive complementary treatment or even an alternative to treat several types of cancers. PDT is based on a reaction involving a photosensitizer (PS), light, and oxygen, which ultimately generates cytotoxic reactive oxygen species (ROS). However, skin photosensitivity, due to the accumulation of PSs in skin cells, has hampered, among other elements, its clinical development and application. Therefore, these is an increasing interest in the use of (metal-based) PSs that are more specific to tumor cells. This may increase efficacy and corollary decrease side-effects. To this end, metal-containing nanoparticles with photosensitizing properties have recently been developed. In addition, several studies have reported that the use of immunogenic/immunomodulatory metal-based nanoparticles increases the antitumor efficacy of immune-checkpoint inhibitor-based immunotherapy mediated by anti-PD-(L)1 or CTLA-4 antibodies. In this review, we discuss the main metal complexes used as PDT PSs. Lastly, we review the preclinical studies associated with metal-based PDT PSs and immunotherapies. This therapeutic association could stimulate PDT.
Language	English
Publishing date	2021-10-26
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics13111788
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Article ; Online: A novel ΔNp63-dependent immune mechanism improves prognosis of HPV-related head and neck cancer.

Mourtada, Jana / Lony, Christelle / Nicol, Anaïs / De Azevedo, Justine / Bour, Cyril / Macabre, Christine / Roncarati, Patrick / Ledrappier, Sonia / Schultz, Philippe / Borel, Christian / Burgy, Mickaël / Wasylyk, Bohdan / Mellitzer, Georg / Herfs, Michaël / Gaiddon, Christian / Jung, Alain C

Frontiers in immunology

2023 Volume 14, Page(s) 1264093

Abstract: Background: Deconvoluting the heterogenous prognosis of Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) is crucial for enhancing patient care, given its rapidly increasing incidence in western countries and the adverse ... ...

Abstract	Background: Deconvoluting the heterogenous prognosis of Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) is crucial for enhancing patient care, given its rapidly increasing incidence in western countries and the adverse side effects of OSCC treatments. Methods: Transcriptomic data from HPV-positive OSCC samples were analyzed using unsupervised hierarchical clustering, and clinical relevance was evaluated using Kaplan-Meier analysis. HPV-positive OSCC cell line models were used in functional analyses and phenotypic assays to assess cell migration and invasion, response to cisplatin, and phagocytosis by macrophages Results: We found, by transcriptomic analysis of HPV-positive OSCC samples, a ΔNp63 dependent molecular signature that is associated with patient prognosis. ΔNp63 was found to act as a tumor suppressor in HPV-positive OSCC at multiple levels. It inhibits cell migration and invasion, and favors response to chemotherapy. RNA-Seq analysis uncovered an unexpected regulation of genes, such as DKK3, which are involved in immune response-signalling pathways. In agreement with these observations, we found that ΔNp63 expression levels correlate with an enhanced anti-tumor immune environment in OSCC, and ΔNp63 promotes cancer cell phagocytosis by macrophages through a DKK3/NF-κB-dependent pathway. Conclusion: Our findings are the first comprehensive identification of molecular mechanisms involved in the heterogeneous prognosis of HPV-positive OSCC, paving the way for much-needed biomarkers and targeted treatment.
MeSH term(s)	Humans ; Human Papillomavirus Viruses ; Papillomavirus Infections/complications ; Carcinoma, Squamous Cell ; Head and Neck Neoplasms/genetics ; Prognosis ; Squamous Cell Carcinoma of Head and Neck/genetics
Language	English
Publishing date	2023-10-25
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.2023.1264093
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Article ; Online: The Microenvironment of Head and Neck Cancers: Papillomavirus Involvement and Potential Impact of Immunomodulatory Treatments.

Outh-Gauer, Sophie / Morini, Aurélien / Tartour, Eric / Lépine, Charles / Jung, Alain C / Badoual, Cécile

Head and neck pathology

2020 Volume 14, Issue 2, Page(s) 330–340

Abstract: Cancer progression can be understood as the result of deregulation of tumors' immune microenvironments. Recent studies of the alterations of microenvironments highlight their significant influence on the prognosis of patients with head and neck squamous ... ...

Abstract	Cancer progression can be understood as the result of deregulation of tumors' immune microenvironments. Recent studies of the alterations of microenvironments highlight their significant influence on the prognosis of patients with head and neck squamous cell carcinoma (HNSCC). It is necessary to better characterize tumor-infiltrating lymphocytes by focusing, in particular, on the tumor escape mechanisms from immune surveillance. One of the best described tumor immune system evasion mechanisms is the expression of co-stimulation molecules that constitute so-called "immune checkpoints". These molecules regulate the immune response by either activating or inhibiting its effects. The programmed cell death 1 (PD-1) surface protein is an inhibitory co-stimulation molecule that induces exhaustion of activated T-lymphocytes (TLs, T cells) through binding with its ligands, PD-L1 and PD-L2. Half of HNSCCs exhibit PD-L1 expression with higher expression identified in human papillomavirus (HPV) positive tumors. Numerous studies have shown differences between the microenvironments of HPV+ and HPV- cancers. Notably, infiltrations of exhausted CD4+ PD1+ and CD8+ PD1+ T cells are far higher in the microenvironment of HPV+ tumors. The FDA has approved the use of molecules that target PD-1 for the treatment of HNSCC. The first results of clinical trials with anti-PD-1 blockers in HNSCC show improved patient survival, particularly long-term survival without recurrence. However, discordant results were sometimes observed, and improvements in defining cellular predictive markers are necessary. With the development of immunotherapies, pathologists play a role in the selection of patients who are eligible for specific treatments and assessment of their prognosis in greater detail. An automated, quantitative in situ imaging system that integrates both multispectral imaging and automated slide scanning could be developed in pathology laboratories. The evaluation of PD-L1 expression has only been used to stratify the administration of first-line immunotherapy. The validation of these tests and their routine interpretation is essential. No specific recommendation is adopted for HPV+ HNSCC.
MeSH term(s)	Alphapapillomavirus ; Humans ; Immunotherapy/methods ; Lymphocytes, Tumor-Infiltrating/drug effects ; Lymphocytes, Tumor-Infiltrating/immunology ; Papillomavirus Infections/immunology ; Squamous Cell Carcinoma of Head and Neck/immunology ; Squamous Cell Carcinoma of Head and Neck/therapy ; Squamous Cell Carcinoma of Head and Neck/virology ; Tumor Escape/drug effects ; Tumor Escape/immunology ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/immunology
Language	English
Publishing date	2020-03-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2407834-7
ISSN	1936-0568 ; 1936-055X
ISSN (online)	1936-0568
ISSN	1936-055X
DOI	10.1007/s12105-020-01147-x
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Article ; Online: Primary, secondary and tertiary prevention of human papillomavirus-driven head and neck cancers.

Mirghani, Haïtham / Jung, Alain C / Fakhry, Carole

European journal of cancer (Oxford, England : 1990)

2017 Volume 78, Page(s) 105–115

Abstract: Human papillomavirus (HPV)-driven oropharyngeal cancers (OPCs) represent an increasing proportion of head and neck cancers that could become, in the next few decades, a public health problem in certain western countries. This significant epidemiological ... ...

Abstract	Human papillomavirus (HPV)-driven oropharyngeal cancers (OPCs) represent an increasing proportion of head and neck cancers that could become, in the next few decades, a public health problem in certain western countries. This significant epidemiological change strongly calls for preventive measures. Prophylactic HPV vaccination and screening programmes for early identification and treatment of premalignant lesions are currently being used to reduce the incidence of uterine cervical cancer, which is the paradigm of HPV-driven malignancy. These strategies have proven to be efficient as the incidence of cervical cancer has dramatically dropped since the 1960s in most countries where they are properly applied. The success of cervical cancer prevention encourages the development of similar approaches to prevent HPV-driven OPCs. However, a number of important limitations impede their application to HPV-driven OPCs, and the development of innovative and specific strategies dedicated to this disease are urgently needed. This article provides an overview on primary, secondary and tertiary prevention of HPV-driven OPC and discusses some directions for future research.
MeSH term(s)	Adolescent ; Adult ; Aged ; Biomarkers, Tumor/metabolism ; DNA, Viral/metabolism ; Early Detection of Cancer/methods ; Female ; Head and Neck Neoplasms/prevention & control ; Head and Neck Neoplasms/virology ; Humans ; Male ; Middle Aged ; Papillomaviridae/genetics ; Papillomavirus Infections/prevention & control ; Papillomavirus Vaccines ; Primary Prevention/methods ; Risk Assessment ; Secondary Prevention/methods ; Tertiary Prevention/methods ; Uterine Cervical Neoplasms/prevention & control ; Uterine Cervical Neoplasms/virology ; Vaccination/statistics & numerical data ; Young Adult
Chemical Substances	Biomarkers, Tumor ; DNA, Viral ; Papillomavirus Vaccines
Language	English
Publishing date	2017-06
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	82061-1
ISSN	1879-0852 ; 0277-5379 ; 0959-8049 ; 0964-1947
ISSN (online)	1879-0852
ISSN	0277-5379 ; 0959-8049 ; 0964-1947
DOI	10.1016/j.ejca.2017.03.021
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Zs.MO 583: Show issues

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Article ; Online: Tumor-Suppressive and Immunomodulating Activity of miR-30a-3p and miR-30e-3p in HNSCC Cells and Tumoroids.

Conrad, Ombline / Burgy, Mickaël / Foppolo, Sophie / Jehl, Aude / Thiéry, Alicia / Guihard, Sébastien / Vauchelles, Romain / Jung, Alain C / Mourtada, Jana / Macabre, Christine / Ledrappier, Sonia / Chenard, Marie-Pierre / Onea, Mihaela-Alina / Danic, Aurélien / Dourlhes, Thomas / Thibault, Claire / Schultz, Philippe / Dontenwill, Monique / Martin, Sophie

International journal of molecular sciences

2023 Volume 24, Issue 13

Abstract: Head and neck squamous cell carcinomas (HNSCCs) are heterogeneous tumors, well known for their frequent relapsing nature. To counter recurrence, biomarkers for early diagnosis, prognosis, or treatment response prediction are urgently needed. miRNAs can ... ...

Abstract	Head and neck squamous cell carcinomas (HNSCCs) are heterogeneous tumors, well known for their frequent relapsing nature. To counter recurrence, biomarkers for early diagnosis, prognosis, or treatment response prediction are urgently needed. miRNAs can profoundly impact normal physiology and enhance oncogenesis. Among all of the miRNAs, the miR-30 family is frequently downregulated in HNSCC. Here, we determined how levels of the 3p passenger strands of miR-30a and miR-30e affect tumor behavior and clarified their functional role in LA-HNSCC. In a retrospective study, levels of miR-30a-3p and miR-30e-3p were determined in 110 patients and correlated to overall survival, locoregional relapse, and distant metastasis. miR-30a/e-3p were expressed in HNSCC cell lines and HNSCC patient-derived tumoroids (PDTs) to investigate their effect on tumor cells and their microenvironment. Both miRNAs were found to have a prognosis value since low miR-30a/e-3p expression correlates to adverse prognosis and reduces overall survival. Low expression of miR-30a/e-3p is associated with a shorter time until locoregional relapse and a shorter time until metastasis, respectively. miR-30a/e-3p expression downregulates both TGF-βR1 and BMPR2 and attenuates the survival and motility of HNSCC. Results were confirmed in PDTs. Finally, secretomes of miR-30a/e-3p-transfected HNSCC activate M1-type macrophages, which exert stronger phagocytic activities toward tumor cells. miR-30a/e-3p expression can discriminate subgroups of LA-HNSCC patients with different prognosis, making them good candidates as prognostic biomarkers. Furthermore, by targeting members of the TGF-β family and generating an immune-permissive microenvironment, they may emerge as an alternative to anti-TGF-β drugs to use in combination with immune checkpoint inhibitors.
MeSH term(s)	Humans ; Squamous Cell Carcinoma of Head and Neck/genetics ; Retrospective Studies ; Head and Neck Neoplasms/genetics ; Neoplasm Recurrence, Local/genetics ; MicroRNAs/genetics ; Gene Expression Regulation, Neoplastic ; Tumor Microenvironment/genetics
Chemical Substances	MicroRNAs
Language	English
Publishing date	2023-07-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241311178
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Article ; Online: The EXTREME Regimen Associating Cetuximab and Cisplatin Favors Head and Neck Cancer Cell Death and Immunogenicity with the Induction of an Anti-Cancer Immune Response.

De Azevedo, Justine / Mourtada, Jana / Bour, Cyril / Devignot, Véronique / Schultz, Philippe / Borel, Christian / Pencreach, Erwan / Mellitzer, Georg / Gaiddon, Christian / Jung, Alain C

Cells

2022 Volume 11, Issue 18

Abstract: 1) Background: The first line of treatment for recurrent/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) has recently evolved with the approval of immunotherapies that target the anti-PD-1 immune checkpoint. However, only about 20% of the ... ...

Abstract	(1) Background: The first line of treatment for recurrent/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) has recently evolved with the approval of immunotherapies that target the anti-PD-1 immune checkpoint. However, only about 20% of the patients display a long-lasting objective tumor response. The modulation of cancer cell immunogenicity via a treatment-induced immunogenic cell death is proposed to potentially be able to improve the rate of patients who respond to immune checkpoint blocking immunotherapies. (2) Methods: Using human HNSCC cell line models and a mouse oral cancer syngeneic model, we have analyzed the ability of the EXTREME regimen (combination therapy using the anti-EGFR cetuximab antibody and platinum-based chemotherapy) to modify the immunogenicity of HNSCC cells. (3) Results: We showed that the combination of cetuximab and cisplatin reduces cell growth through both cell cycle inhibition and the induction of apoptotic cell death independently of p53. In addition, different components of the EXTREME regimen were found to induce, to a variable extent, and in a cell-dependent manner, the emission of mediators of immunogenic cell death, including calreticulin, HMGB1, and type I Interferon-responsive chemokines. Interestingly, cetuximab alone or combined with the IC
MeSH term(s)	Animals ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Apoptosis ; Calreticulin ; Cetuximab/therapeutic use ; Cisplatin/therapeutic use ; HMGB1 Protein ; Head and Neck Neoplasms/drug therapy ; Head and Neck Neoplasms/immunology ; Humans ; Immunity ; Interferon Type I ; Mice ; Neoplasm Recurrence, Local/pathology ; Squamous Cell Carcinoma of Head and Neck/drug therapy ; Tumor Suppressor Protein p53
Chemical Substances	Calreticulin ; HMGB1 Protein ; Interferon Type I ; Tumor Suppressor Protein p53 ; Cetuximab (PQX0D8J21J) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2022-09-14
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11182866
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