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1. Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity

Author

Cara Haymaker, Jason Roszik, Jie Qing Chen, Jahan Khalili, Zhe Wang, Nikunj Satani, Rina M. Mbofung, Laurence J.N. Cooper, Marie-Andree Forget, Willem W. Overwijk, Chunyu Xu, Leila Williams, Weiyi Peng, Chengwen Liu, Deborah A. Silverman, Simone Punt, Sourindra Maiti, Florian L. Muller, Elien M Doorduijn, Chantale Bernatchez, Trang N. Tieu, Ana Lucia Dominguez, Soraya Zorro Manrique, Patrick Hwu, Shruti Malu, Emily Ashkin, Jodi A. McKenzie, Rodabe N. Amaria, and Timothy P. Heffernan

Subjects
Cancer Research, High-throughput screen, medicine.medical_treatment, Immunology, Apoptosis, Mice, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Aurora kinase, In vivo, Tumor Cells, Cultured, Tumor Microenvironment, medicine, Animals, Aurora Kinase B, Humans, Immunology and Allergy, Cytotoxicity, Melanoma, Aurora Kinase A, Cell Proliferation, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, Chemistry, T-cell cytotoxicity, Immunotherapy, Prognosis, medicine.disease, Xenograft Model Antitumor Assays, Survival Rate, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer research, Original Article, Female, T cell mediated cytotoxicity, Immune checkpoint blockade, T-Lymphocytes, Cytotoxic
Abstract

Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated. Gene expression analyses were performed on tumor samples from patients undergoing immunotherapy for metastatic melanoma. Finally, the effect of inhibiting the top targets on the efficacy of immunotherapy was investigated in multiple preclinical models. Aurora kinase was identified as a mediator of melanoma cell resistance to T-cell-mediated cytotoxicity in both complementary screens. Aurora kinase inhibitors were validated to synergize with T-cell-mediated cytotoxicity in vitro. The Aurora kinase inhibition-mediated sensitivity to T-cell cytotoxicity was shown to be partially driven by p21-mediated induction of cellular senescence. The expression levels of Aurora kinase and related proteins were inversely correlated with immune infiltration, response to immunotherapy and survival in melanoma patients. Aurora kinase inhibition showed variable responses in combination with immunotherapy in vivo, suggesting its activity is modified by other factors in the tumor microenvironment. These data suggest that Aurora kinase inhibition enhances T-cell cytotoxicity in vitro and can potentiate antitumor immunity in vivo in some but not all settings. Further studies are required to determine the mechanism of primary resistance to this therapeutic intervention. Electronic supplementary material The online version of this article (10.1007/s00262-020-02748-9) contains supplementary material, which is available to authorized users.

Published
2020
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2. MeMoVolc report on classification and dynamics of volcanic explosive eruptions

Author

Antonio Costa, Margherita Polacci, Céline Vidal, Barbara Tripoli, Lucia Dominguez, Katharine V. Cashman, Simona Scollo, Laura Pioli, Daniele Andronico, J. L. Le Pennec, Roberto Sulpizio, Sébastien Biass, Gholamhossein Bagheri, Nicolau Wallenstein, Eduardo Rossi, Andrew J. L. Harris, Jeremy C. Phillips, Guido Giordano, Giovanni Macedonio, Matthias Hort, Ármann Höskuldsson, Maurizio Ripepe, Costanza Bonadonna, Irene Manzella, Raffaello Cioni, Greg A. Valentine, Bettina Scheu, Olivier Bachmann, Augusto Neri, Michael Manga, Marco Pistolesi, Jean-Christophe Komorowski, U. Küppers, M. de' Michieli Vitturi, Bruce F. Houghton, Olivier Galland, Tobias Dürig, Timothy H. Druitt, Sébastien Valade, Magnús T. Gudmundsson, Federico Brogi, Giorgio Lacanna, Section des Sciences de la Terre et de l'environnement, Université de Genève = University of Geneva (UNIGE), CNR Institute of Geosciences and Earth Resources (IGG), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Istituto Nazionale di Geofisica e Vulcanologia - Sezione di Catania (INGV), Istituto Nazionale di Geofisica e Vulcanologia, Laboratoire Magmas et Volcans (LMV), Observatoire de Physique du Globe de Clermont-Ferrand (OPGC), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Institute of Geochemistry and Petrology [ETH Zürich], Department of Earth Sciences [Swiss Federal Institute of Technology - ETH Zürich] (D-ERDW), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Department of Geology and Geophysics (SOEST), University of Hawai‘i [Mānoa] (UHM), Géosciences Rennes (GR), Université de Rennes (UR)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre Armoricain de Recherches en Environnement-Centre National de la Recherche Scientifique (CNRS), Institute of Earth Sciences [Reykjavik], University of Iceland [Reykjavik], OV-INGV, Department of Earth and Planetary Science [UC Berkeley] (EPS), University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC), Sezione di Palermo, Dipartimento di Scienze della Terra [Firenze] (DST), Università degli Studi di Firenze = University of Florence (UniFI), Department of Earth and Environmental Sciences [München], Ludwig-Maximilians-Universität München (LMU), IDPA-CNR, Bonadonna, C., Cioni, R., Costa, A., Druitt, T., Phillips, J., Pioli, Luca, Andronico, D., Harris, A., Scollo, S., Bachmann, O., Bagheri, G., Biass, S., Brogi, F., Cashman, K., Dominguez, L., Dürig, T., Galland, O., Giordano, Guido, Gudmundsson, M., Hort, M., Höskuldsson, A., Houghton, B., Komorowski, J. C., Küppers, U., Lacanna, G., Le Pennec, J. L., Macedonio, G., Manga, M., Manzella, I., Vitturi, M. de’ Michieli, Neri, A., Pistolesi, M., Polacci, M., Ripepe, M., Rossi, E., Scheu, B., Sulpizio, Roberto, Tripoli, B., Valade, S., Valentine, G., Vidal, C., Wallenstein, N., Université de Genève (UNIGE), Consiglio Nazionale delle Ricerche (CNR), Institut national des sciences de l'Univers (INSU - CNRS)-Université Jean Monnet [Saint-Étienne] (UJM)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Observatoire de Physique du Globe de Clermont-Ferrand (OPGC), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institute of Geochemistry and Petrology, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre Armoricain de Recherches en Environnement-Centre National de la Recherche Scientifique (CNRS), University of California [Berkeley], University of California-University of California, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), and Department of Earth Systems Analysis

Subjects
Geochemistry & Geophysics, Cinder cone, 010504 meteorology & atmospheric sciences, Lava, Earth science, Pyroclastic rock, Eruption dynamics, Volcanism, 010502 geochemistry & geophysics, 01 natural sciences, Geochemistry and Petrology, Eruption classification, Eruptive processes, Eruptive products, Eruptive styles, ITC-CV, ddc:550, [SDU.STU.VO]Sciences of the Universe [physics]/Earth Sciences/Volcanology, Caldera, 0105 earth and related environmental sciences, ddc:333.7-333.9, geography, geography.geographical_feature_category, Explosive eruption, Geology, Volcanology, Volcano, 13. Climate action
Abstract

© 2016, Springer-Verlag Berlin Heidelberg. Classifications of volcanic eruptions were first introduced in the early twentieth century mostly based on qualitative observations of eruptive activity, and over time, they have gradually been developed to incorporate more quantitative descriptions of the eruptive products from both deposits and observations of active volcanoes. Progress in physical volcanology, and increased capability in monitoring, measuring and modelling of explosive eruptions, has highlighted shortcomings in the way we classify eruptions and triggered a debate around the need for eruption classification and the advantages and disadvantages of existing classification schemes. Here, we (i) review and assess existing classification schemes, focussing on subaerial eruptions; (ii) summarize the fundamental processes that drive and parameters that characterize explosive volcanism; (iii) identify and prioritize the main research that will improve the understanding, characterization and classification of volcanic eruptions and (iv) provide a roadmap for producing a rational and comprehensive classification scheme. In particular, classification schemes need to be objective-driven and simple enough to permit scientific exchange and promote transfer of knowledge beyond the scientific community. Schemes should be comprehensive and encompass a variety of products, eruptive styles and processes, including for example, lava flows, pyroclastic density currents, gas emissions and cinder cone or caldera formation. Open questions, processes and parameters that need to be addressed and better characterized in order to develop more comprehensive classification schemes and to advance our understanding of volcanic eruptions include conduit processes and dynamics, abrupt transitions in eruption regime, unsteadiness, eruption energy and energy balance.

Published
2016
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