Head of the team "Host-tumor interactions in Head and Neck Carcinoma"
Deputy head of the UMR9018 METSY unit
Head of the team "Host-tumor relationships in head and neck carcinomas: exploration and therapeutic modulations"
PR1 UP SACLAY
Our research is mainly oriented towards host-tumor interactions envisioned at the scale of the whole organism (tumor macro-environment). A first series of studies aims to elucidate the mechanisms of several deleterious effects exerted remotely by malignant cells: inhibitory effects on the immune system and induction of muscle atrophy. A second series of works is more oriented towards therapeutic applications: it aims to produce and characterize new recombinant adenoviruses to promote tumor destruction while minimizing systemic adverse effects.
A – First part: remote effects of malignant cells on the immune system and skeletal muscles (P. Busson, T. Ragot)
For the last 10 years, most research projects carried in P. Busson’s group have been focused on extracellular galectin-9 (gal-9), a protein with immunosuppressive activity, often produced inappropriately by malignant cells, in particular in certain Head and Neck carcinomas (HNCs)(Baloche et al., Sci Rep 2021; doi.10.1038/s41598-021-84270-1)(Tran et al., Oncoimmunology 2022; doi: 10.1080/2162402X.2022.2150472). However, the effects of extracellular gal-9 are not entirely immunosuppressive. Recent results indicate that it may play a role in the development of germinal centers (Tran et al., manuscript in preparation). One extension of our experimental and translational research on gal-9 is the development of a neutralizing antibody for therapeutic purposes. It is carried out in collaboration with two companies, HiFibiO Therapeutics and FibroGen, on the basis of a patent in which our group holds about 50% of the inventive shares (W02015185875A3) (Lhuillier et al., Plos One 2018; doi: 10.1371/journal.pone.0202512).
More recently, we became interested in the mechanisms of muscular atrophy or sarcopenia which is very common in the context of HNCs. It is a factor of poor prognosis which often prevents the implementation of potentially effective anti-tumor treatments (chemotherapy, immunotherapy…). Our study is based both on in vitro co-culture experiments and on the use of small muscle fragments collected during surgery in patients with HNCs. Thus, we were able to observe similar transcriptional alterations in muscle cells co-cultured with malignant cells in vitro and in muscle fragments from patients presenting with a sarcopenic state (H. Hachicha and I. Baïche, manuscript in preparation).
B – Development of viral antitumor strategies (K. Benihoud, S. Dupré-Crochet and T. Ragot)
The first line of research aims to better understand the interactions of different adenoviral serotypes with host cells, both malignant cells and those of the immune system. We are particularly interested in the interactions of different adenovirus serotypes with neutrophils. Indeed, if the interaction of neutrophils with bacteria and fungi is well studied, few studies have focused on the interaction of neutrophils with viruses. In particular, our work seeks to better understand the reciprocal interactions between adenoviruses and neutrophils and to assess whether neutrophils influence anti-adenovirus immunity. In this first line of research, we are also interested in the development of new adenoviral vectors allowing better targeting of tumor cells. Finally, we are exploring the use of electric fields to increase adenovirus penetration into insensitive cells (Tesse et al. Sci Rep 2021; doi: 10.1038/s41598-021-96781-y).
The second line of research aims to assess the ability of oncolytic adenoviruses to stimulate anti-tumor immune responses in Head and Neck carcinoma models. This immunovirotherapy approach exploits the ability of oncolytic adenoviruses to selectively replicate in malignant cells and release tumor antigens to induce anti-tumor immune responses.
The third line of research aims to develop vaccination approaches based mainly on the exposure of antigens on the surface of viral capsids. Thus, we have shown that adenoviruses carrying epitopes inserted into their capsid proteins generate strong humoral and cellular immune responses (Anchim et al. Frontiers in Immunology 2018; doi: 10.3389/fimmu.2018.00124). More recently, as part of a collaboration with the team of Pascale Boulanger (CNRS, I2BC CNRS UMR 9198), we showed that phage capsids displaying a model antigen on their surface induced strong immune responses against this antigen (patent WO2021053309, Vernhes et al. submitted). Our current work aims to analyze the ability of these vaccine platforms to induce immune responses in Head and Neck carcinoma models.
MC UP SACLAY
Post Doc HIFIBIO
PhD student UP SACLAY
PhD student UP SACLAY
Zapletal E, Vasiljevic T, Busson P, Matijevic Glavan T. Dialog beyond the Grave: Necrosis in the Tumor Microenvironment and Its Contribution to Tumor Growth. Int J Mol Sci. 2023 Mar 9;24(6):5278. doi: 10.3390/ijms24065278.
Xu JX, Zhang R, Huang DJ, Tang Y, Ping LQ, Huang BJ, Huang HQ, Busson P, Li J. Galectin-9 Facilitates Epstein-Barr Virus Latent Infection and Lymphomagenesis in Human B Cells. Microbiol Spectr. 2023 Feb 14;11(1):e0493222. doi: 10.1128/spectrum.04932-22.
Kapetanakis NI, Busson P. Galectins as pivotal components in oncogenesis and immune exclusion in human malignancies. Front Immunol. 2023 Feb 3;14:1145268. doi: 10.3389/fimmu.2023.1145268.
Nielsen MA, Køster D, Mehta AY, Stengaard-Pedersen K, Busson P, Junker P, Hørslev-Petersen K, Hetland ML, Østergaard M, Hvid M, Leffler H, Kragstrup TW, Cummings RD, Deleuran B. Increased Galectin-9 Levels Correlate with Disease Activity in Patients with DMARD-Naïve Rheumatoid Arthritis and Modulate the Secretion of MCP-1 and IL-6 from Synovial Fibroblasts. Cells. 2023 Jan 15;12(2):327. doi: 10.3390/cells12020327.
Tran BT, Gelin A, Durand S, Texier M, Daste A, Toullec C, Benihoud K, Breuskin I, Gorphe P, Garic F, Brenner C, Le Tourneau C, Fayette J, Niki T, David M, Busson P, Even C. Plasma galectins and metabolites in advanced head and neck carcinomas: evidence of distinct immune characteristics linked to hypopharyngeal tumors. Oncoimmunology. 2022 Dec 17;12(1):2150472. doi: 10.1080/2162402X.2022.2150472.
Mellouk A, Hutteau-Hamel T, Legrand J, Safya H, Benbijja M, Mercier-Nomé F, Benihoud K, Kanellopoulos JM, Bobé P. P2X7 purinergic receptor plays a critical role in maintaining T-cell homeostasis and preventing lupus pathogenesis. Front Immunol. 2022 Sep 29;13:957008. doi: 10.3389/fimmu.2022.957008.
Nestić D, Hozić A, Brkljača Z, Butorac A, Pažur K, Jullienne B, Cindrić M, Ambriović-Ristov A, Benihoud K, Majhen D. Integrin αvβ3 and disulfide bonds play important roles in NGR-retargeted adenovirus transduction efficiency. Life Sci. 2022 Feb 15;291:120116. doi: 10.1016/j.lfs.2021.120116.
Jorapur A, Marshall LA, Jacobson S, Xu M, Marubayashi S, Zibinsky M, Hu DX, Robles O, Jackson JJ, Baloche V, Busson P, Wustrow D, Brockstedt DG, Talay O, Kassner PD, Cutler G. EBV+ tumors exploit tumor cell-intrinsic and -extrinsic mechanisms to produce regulatory T cell-recruiting chemokines CCL17 and CCL22. PLoS Pathog. 2022 Jan 13;18(1):e1010200. doi: 10.1371/journal.ppat.1010200.
Pánisová E, Lünemann A, Bürgler S, Kotur M, Lazarovici J, Danu A, Kaulfuss M, Mietz J, Chijioke O, Münz C, Busson P, Berger C, Ghez D, Azzi T. Reduced frequency of cytotoxic CD56dim CD16+ NK cells leads to impaired antibody-dependent degranulation in EBV-positive classical Hodgkin lymphoma. Cancer Immunol Immunother. 2022 Jan;71(1):13-24. doi: 10.1007/s00262-021-02956-x.
Emanuel O, Liu J, Schartinger VH, Nei WL, Chan YY, Tsang CM, Riechelmann H, Masterson L, Haybaeck J, Oppermann U, Willems SM, Ooft ML, Wollmann G, Howard D, Vanhaesebroeck B, Lund VJ, Royle G, Chua MLK, Lo KW, Busson P, Lechner M. SSTR2 in Nasopharyngeal Carcinoma: Relationship with Latent EBV Infection and Potential as a Therapeutic Target. Cancers (Basel). 2021 Sep 30;13(19):4944. doi: 10.3390/cancers13194944.
Makowska A, Lelabi N, Nothbaum C, Shen L, Busson P, Tran TTB, Eble M, Kontny U. Radiotherapy Combined with PD-1 Inhibition Increases NK Cell Cytotoxicity towards Nasopharyngeal Carcinoma Cells. Cells. 2021 Sep 17;10(9):2458. doi: 10.3390/cells10092458.
Tesse A, André FM, Ragot T. Aluminum particles generated during millisecond electric pulse application enhance adenovirus-mediated gene transfer in L929 cells. Sci Rep. 2021 Sep 6;11(1):17725. doi: 10.1038/s41598-021-96781-y.
Baloche V, Rivière J, Tran TBT, Gelin A, Bawa O, Signolle N, Diop MBK, Dessen P, Beq S, David M, Busson P. Serial transplantation unmasks galectin-9 contribution to tumor immune escape in the MB49 murine model. Sci Rep. 2021 Mar 4;11(1):5227. doi: 10.1038/s41598-021-84270-1.
Makowska A, Meier S, Shen L, Busson P, Baloche V, Kontny U. Anti-PD-1 antibody increases NK cell cytotoxicity towards nasopharyngeal carcinoma cells in the context of chemotherapy-induced upregulation of PD-1 and PD-L1. Cancer Immunol Immunother. 2021 Feb;70(2):323-336. doi: 10.1007/s00262-020-02681-x.
Zhang CX, Huang DJ, Baloche V, Zhang L, Xu JX, Li BW, Zhao XR, He J, Mai HQ, Chen QY, Zhang XS, Busson P, Cui J, Li J. Galectin-9 promotes a suppressive microenvironment in human cancer by enhancing STING degradation. Oncogenesis. 2020 Jul 6;9(7):65. doi: 10.1038/s41389-020-00248-0.
Baloche V, Ferrand FR, Makowska A, Even C, Kontny U, Busson P. Emerging therapeutic targets for nasopharyngeal carcinoma: opportunities and challenges. Expert Opin Ther Targets. 2020 Jun;24(6):545-558. doi: 10.1080/14728222.2020.1751820.