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

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.

• Authors: Simone Punt, Shruti Malu, Jodi A McKenzie, Soraya Zorro Manrique, Elien M Doorduijn, Rina M Mbofung, Leila Williams, Deborah A Silverman, Emily L Ashkin, Ana Lucía Dominguez, Zhe Wang, Jie Qing Chen, Sourindra N Maiti, Trang N Tieu, Chengwen Liu, Chunyu Xu, Marie-Andrée Forget, Cara Haymaker, Jahan S Khalili, Nikunj Satani, Florian Muller, Laurence J N Cooper, Willem W Overwijk, Rodabe N Amaria, Chantale Bernatchez, Timothy P Heffernan, Weiyi Peng, Jason Roszik, Patrick Hwu
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 70 Issue 4 Pg. 1101-1113 (Apr 2021) ISSN: 1432-0851 [Electronic] Germany
• PMID: 33123754 (Publication Type: Journal Article)

Chemical References

• AURKA protein, human
• AURKB protein, human
• Aurora Kinase A
• Aurora Kinase B

Topics

• Animals
• Apoptosis
• Aurora Kinase A (antagonists & inhibitors, genetics, metabolism)
• Aurora Kinase B (antagonists & inhibitors, genetics, metabolism)
• Cell Proliferation
• Drug Resistance, Neoplasm (immunology)
• Female
• Humans
• Immunotherapy (methods)
• Lymphocytes, Tumor-Infiltrating (immunology)
• Melanoma (genetics, immunology, metabolism, therapy)
• Mice
• Prognosis
• Survival Rate
• T-Lymphocytes, Cytotoxic (immunology, transplantation)
• Tumor Cells, Cultured
• Tumor Microenvironment (immunology)
• Xenograft Model Antitumor Assays