Team 12

MITIC, Manipulation of Lymphocytes for Immunotherapy

Team Leaders: Emmanuel Scotet and Christelle Harly

For many years, Team MITIC has been developing complementary research programs in immunology with a particular focus on human lymphoid populations, such as various T cell subsets (eg. gamma delta T, NK-T cells) or NK cells. These research axes aim at understanding the biology, the functions, and the regulation of these immune cell subsets, as well as investigating their immunotherapeutic potential especially in oncological contexts (e.g. hematological and brain tumors, breast and ovary cancers). During the last years, an interest was also taken for the analysis of developmental pathways and transcriptional programs of innate lympoid cells, as well as the design of various molecular approaches to manipulate lymphoid subsets for immunotherapies (e.g. gene editing, transcriptional reprogramming). Some of our programs are dedicated to the functional analysis and the molecular engineering of biological molecules, such as cytokines and antibodies. Other research projects aim at understanding the environmental factors and signals that regulate the biology, activation and functions of diverse lymphoid cell subsets, especially in oncological or immune disorder/auto-immune indications. Finally, our team leads, or is involved in, different clinical trials in tumor or auto-immune pathological contexts.

The results obtained in these different domains enabled Team MITIC to position itself, both nationally and internationally, as an important player in fundamental and applied immunology research in the field of lymphoid population biology and their exploitation in immunotherapies. This recognition is reflected by: (i) its membership in many national collaborative programs funded, some of them in portage (ii) the direction, the management or the membership in various consortia or structures at the local or national level, (iii) co-leadership and participation in national and international thematic networks. These activities are carried out in collaboration with numerous groups/institutes at the local, national and international levels. This recognition is also illustrated by the involvement of many members of the team not only in university teaching activities and in the organization of conferences but also their participation in expertise activities or consultancy. Concerning knowledge transfer, the team is developing a growing number of industrial partnerships or clinical partnerships, which also allow it to finance and valorize its research activities.

Makanga DR, Jullien M, David G, Legrand N, Willem C, Dubreuil L, Walencik A, Touzeau C, Gastinne T, Tessoulin B, Le Gouill S, Mahé B, Gagne K, Chevallier P, Clemenceau B, Retière C. 2022. Low number of KIR ligands in lymphoma patients favors a good rituximab-dependent NK cell response. Oncoimmunology. 14;10(1):1936392. doi: 10.1080/2162402X.2021.1936392.

Harly C, Joyce SP, Domblides C, Bachelet T, Pitard V, Mannat C, Pappalardo A, Couzi L, Netzer S, Massara L, Obre E, Hawchar O, Lartigue L, Claverol S, Cano C, Moreau JF, Mahouche I, Soubeyran I, Rossignol R, Viollet B, Willcox CR, Mohammed F, Willcox BE, Faustin B, Déchanet-Merville J. 2021. Human γδ T cell sensing of AMPK-dependent metabolic tumor reprogramming through TCR recognition of EphA2. Sci Immunol. 6(61):eaba9010. doi: 10.1126/sciimmunol.aba9010.

Rafia C, Harly C, Scotet E. 2020. Beyond CAR T cells: engineered Vγ9Vδ2 T cells to fight solid tumors. Immunol Rev. 298:117-133. doi: 10.1111/imr.12920.

Perroteau J, Navet B, Devilder MC, Hesnard L, Scotet E, Gapin L, Saulquin X, Gautreau-Rolland L. 2020. Contribution of the SYK Tyrosine kinase expression to human iNKT self-reactivity. Eur J Immunol. 50(10):1454-1467. doi: 10.1002/eji.201948416.

Makanga DR, Guillaume T, Willem C, Legrand N, Gagne K, Cesbron A, Gendzekhadze K, Peterlin P, Garnier A, Le Bourgeois A, Béné MC, Chevallier P, Retière C. 2020. PTCY and ATG versus PTCY as GVHD prophylaxis for peripheral blood stem cells haploidentical transplants: comparison of T-cell and NK effectors reconstitution. J Immunol. 205(5):1441-1448. doi: 10.4049/jimmunol.2000578.

Dustin ML, Scotet E, Olive D. 2019. An X-ray Vision for Phosphoantigen Recognition. Immunity. 50(4):1026-1028. doi: 10.1016/j.immuni.2019.03.015.

Devilder MC, Moyon M, Gautreau L, Navet B, Perroteau J, Delbos F, Gesnel MC, Breathnach R, Saulquin X. 2019. Ex vivo Evolution of Human Antibodies by CRISPR-X: from a naive B cell repertoire to affinity matured antibodies. BMC Biotechnol. 19(1):14. doi: 10.1186/s12896-019-0504-z.

Harly C, Kenney D, Ren G, Lai B, Raabe T, Yang Q, Cam MC, Xue HH, Zhao K, Bhandoola A. 2019. The transcription factor TCF-1 enforces commitment to the innate lymphoid cell lineage. Nat Immunol. 20(9):1150-1160. doi: 10.1038/s41590-019-0445-7.

Chauvin C, Joalland N, Perroteau J, Jarry U, Lafrance L, Willem C, Retière C, Oliver L, Gratas C, Gautreau-Rolland L, Saulquin X, Vallette FM, Vié H, Scotet E, Pecqueur C. 2019. NKG2D controls natural reactivity of Vγ9Vδ2 T lymphocytes against mesenchymal glioblastoma cells. Clin Cancer Res. 25(23):7218-7228. doi: 10.1158/1078-0432.CCR-19-0375.

Willem C, Makanga DR, Guillaume T, Maniangou B, Legrand N, Gagne K,Peterlin P, Garnier A, Béné MC,Cesbron A, Le Bourgeois A, Chevallier P* and Retiere C*. 2019. Impact of KIR/HLA Incompatibilities on NK Cell Reconstitution and Clinical Outcome after T Cell–Replete Haploidentical Hematopoietic Stem Cell Transplantation with Posttransplant Cyclophosphamide. J Immunol. 202(7):2141-2152. doi: 10.4049/jimmunol.1801489.

Quémémer A, Morisseau S, Sousa RP, Trillet K, Maillasson M, Leray I, Jacques Y, Dion J, Barbieux I, Frutoso M, Laurent AD, Le Questel JY, Mortier E. 2019. IL-15Ra membrane-anchorage either in cis or trans is required for stabilization of IL-15 and optimal signaling. J. Cell. Sci. 133(5):jcs236802. doi: 10.1242/jcs.236802.

Frutoso M., Morisseau S., Tamzalit F., Leray I., Quéméner A., Jacques Y., and Mortier E. 2018. Critical role of CD8 T cells on NK cell responsiveness to cytokine re-stimulation in vivo. J Immunol. 201(2): 493-506. doi: 10.4049/jimmunol.1800086.

Ollier J, Vivien R, Vié H, Clémenceau B. 2017. Transfection of FcγRIIIa (CD16) Alone Can Be Sufficient To Enable Human αβTCR T Lymphocytes To Mediate Antibody-Dependent Cellular Cytotoxicity. ImmunoHorizons. 1(5) 63-70. doi.org/10.4049/immunohorizons.1700022.

Quéméner A, Maillasson M, Arzel L, Sicard B, Vomiandry R, Mortier E, Dubreuil D, Jacques Y, Lebreton J, Mathe M. 2017. Discovery of a Small-Molecule Inhibitor of IL-15: Pharmacophore-Based Virtual Screening and Hit Optimization. J. Med. Chem. 60(14):6249-6272. doi: 10.1021/acs.jmedchem.7b00485.

Ouisse LH, Gautreau-Rolland L, Devilder MC, Osborn M, Moyon M, Visentin J, Halary F, Bruggemann M, Buelow R, Anegon I, Saulquin X. 2017. Antigen-specific single B cell sorting and expression-cloning from immunoglobulin humanized rats: a rapid and versatile method for the generation of high affinity and discriminative human monoclonal antibodies. BMC Biotechnol. 17(1):3. doi: 10.1186/s12896-016-0322-5.

Jarry U, Chauvin C, Joalland N, Léger A, Minault S, Robard M, Bonneville M, Oliver L, Vallette FM, Vié H, Pecqueur C, Scotet E. 2016. Stereotaxic administrations of allogeneic human Vγ9Vδ2 T cells efficiently control the development of human glioblastoma brain tumors. Oncoimmunology. 5(6):e1168554. doi: 10.1080/2162402X.2016.1168554.

Hesnard L, Legoux F, Gautreau L, Moyon M, Baron O, Devilder MC, Bonneville M, Saulquin X. 2016. Role of the MHC restriction during maturation of antigen-specific human T cells in the thymus. Eur J Immunol. (3):560-569. doi: 10.1002/eji.201545951.

Clémenceau B, Valsesia-Wittmann S, Jallas AC, Vivien R, Rousseau R, Marabelle A, Caux C, Vié H. 2015. In Vitro and In Vivo Comparison of Lymphocytes Transduced with a Human CD16 or with a Chimeric Antigen Receptor Reveals Potential Off-Target Interactions due to the IgG2 CH2-CH3 CAR-Spacer. J Immunol Res. 2015:482089. doi: 10.1155/2015/482089.