Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity
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ORIGINAL ARTICLE
Aurora kinase inhibition sensitizes melanoma cells to T‑cell‑mediated cytotoxicity Simone Punt1 · Shruti Malu1,8 · Jodi A. McKenzie1,9 · Soraya Zorro Manrique1 · Elien M. Doorduijn1 · Rina M. Mbofung1,10 · Leila Williams1,11 · Deborah A. Silverman1 · Emily L. Ashkin1 · Ana Lucía Dominguez1 · Zhe Wang1,12 · Jie Qing Chen1,13 · Sourindra N. Maiti2 · Trang N. Tieu3,14 · Chengwen Liu1 · Chunyu Xu1,15 · Marie‑Andrée Forget1 · Cara Haymaker1 · Jahan S. Khalili1,16 · Nikunj Satani4 · Florian Muller4 · Laurence J. N. Cooper2,17 · Willem W. Overwijk1,18 · Rodabe N. Amaria1 · Chantale Bernatchez1 · Timothy P. Heffernan3 · Weiyi Peng1,15 · Jason Roszik5 · Patrick Hwu1,6,7 Received: 5 May 2020 / Accepted: 13 October 2020 © The Author(s) 2020
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. Keywords Aurora kinase · Melanoma · Immunotherapy · High-throughput screen · Immune checkpoint blockade · T-cell cytotoxicity
Introduction
Simone Punt and Shruti Malu contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02748-9) contains supplementary material, which is available to authorized users. * Patrick Hwu [email protected] Extended author information available on
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