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Article

Targeting Replication Stress Using CHK1 Inhibitor Promotes Innate and NKT Cell Immune Responses and Tumour Regression

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Mater Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia
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The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD 4102, Australia
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Mater Pathology, Mater Research, Mater Hospital, Raymond Terrace, South Brisbane, QLD 4101, Australia
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Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
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Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
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Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC 3010, Australia
*
Author to whom correspondence should be addressed.
Cancers 2021, 13(15), 3733; https://doi.org/10.3390/cancers13153733
Received: 13 July 2021 / Revised: 20 July 2021 / Accepted: 22 July 2021 / Published: 25 July 2021
(This article belongs to the Section Cancer Therapy)
Therapies selectively targeting cancer-specific defects have the advantage of minimising damage to normal tissue including the immune system. The work described here investigates a therapy that targets replication stress, a common feature of many cancer types including melanoma. We demonstrate that this therapy not only selectively kills tumours but also triggers pro-immunogenic signals from the tumour to attract immune cells. In animal models, it has no adverse effects on immune response and triggers a strong anti-tumour immune response. The major component of this response are specialised immune cells, but the tumour itself trigger a conversion of this anti-tumour response to an immune suppressive response that cannot be overcome with current immunotherapies. The work demonstrates that understanding the immune response triggered is essential to guide the selection of the optimal immunotherapy to promote long term tumour control.
Drugs selectively targeting replication stress have demonstrated significant preclinical activity, but this has not yet translated into an effective clinical treatment. Here we report that targeting increased replication stress with a combination of Checkpoint kinase 1 inhibitor (CHK1i) with a subclinical dose of hydroxyurea targets also promotes pro-inflammatory cytokine/chemokine expression that is independent of cGAS-STING pathway activation and immunogenic cell death in human and murine melanoma cells. In vivo, this drug combination induces tumour regression which is dependent on an adaptive immune response. It increases cytotoxic CD8+ T cell activity, but the major adaptive immune response is a pronounced NKT cell tumour infiltration. Treatment also promotes an immunosuppressive tumour microenvironment through CD4+ Treg and FoxP3+ NKT cells. The number of these accumulated during treatment, the increase in FoxP3+ NKT cells numbers correlates with the decrease in activated NKT cells, suggesting they are a consequence of the conversion of effector to suppressive NKT cells. Whereas tumour infiltrating CD8+ T cell PD-1 and tumour PD-L1 expression was increased with treatment, peripheral CD4+ and CD8+ T cells retained strong anti-tumour activity. Despite increased CD8+ T cell PD-1, combination with anti-PD-1 did not improve response, indicating that immunosuppression from Tregs and FoxP3+ NKT cells are major contributors to the immunosuppressive tumour microenvironment. This demonstrates that therapies targeting replication stress can be well tolerated, not adversely affect immune responses, and trigger an effective anti-tumour immune response. View Full-Text
Keywords: melanoma; CHK1 inhibitor; replication stress; immunogenic cell death; innate immune response; adaptive immune response; NKT cells melanoma; CHK1 inhibitor; replication stress; immunogenic cell death; innate immune response; adaptive immune response; NKT cells
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MDPI and ACS Style

Proctor, M.; Gonzalez Cruz, J.L.; Daignault-Mill, S.M.; Veitch, M.; Zeng, B.; Ehmann, A.; Sabdia, M.; Snell, C.; Keane, C.; Dolcetti, R.; Haass, N.K.; Wells, J.W.; Gabrielli, B. Targeting Replication Stress Using CHK1 Inhibitor Promotes Innate and NKT Cell Immune Responses and Tumour Regression. Cancers 2021, 13, 3733. https://doi.org/10.3390/cancers13153733

AMA Style

Proctor M, Gonzalez Cruz JL, Daignault-Mill SM, Veitch M, Zeng B, Ehmann A, Sabdia M, Snell C, Keane C, Dolcetti R, Haass NK, Wells JW, Gabrielli B. Targeting Replication Stress Using CHK1 Inhibitor Promotes Innate and NKT Cell Immune Responses and Tumour Regression. Cancers. 2021; 13(15):3733. https://doi.org/10.3390/cancers13153733

Chicago/Turabian Style

Proctor, Martina, Jazmina L. Gonzalez Cruz, Sheena M. Daignault-Mill, Margaret Veitch, Bijun Zeng, Anna Ehmann, Muhammed Sabdia, Cameron Snell, Colm Keane, Riccardo Dolcetti, Nikolas K. Haass, James W. Wells, and Brian Gabrielli. 2021. "Targeting Replication Stress Using CHK1 Inhibitor Promotes Innate and NKT Cell Immune Responses and Tumour Regression" Cancers 13, no. 15: 3733. https://doi.org/10.3390/cancers13153733

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