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Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity
- Source :
- Cancer Immunology, Immunotherapy
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 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. Electronic supplementary material The online version of this article (10.1007/s00262-020-02748-9) contains supplementary material, which is available to authorized users.
- 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
Subjects
Details
- ISSN :
- 14320851 and 03407004
- Volume :
- 70
- Database :
- OpenAIRE
- Journal :
- Cancer Immunology, Immunotherapy
- Accession number :
- edsair.doi.dedup.....3754ee295e6a1dfb75f4b44d53a14037