Article | Published:

Translational Therapeutics

STING agonist therapy in combination with PD-1 immune checkpoint blockade enhances response to carboplatin chemotherapy in high-grade serous ovarian cancer

British Journal of Cancervolume 119pages440449 (2018) | Download Citation

Abstract

Background

High-grade serous carcinoma (HGSC) of the ovary is predominantly diagnosed at late stages and primarily treated with debulking surgery followed by platinum/taxane-based chemotherapy. Although certain patients benefit significantly from currently used chemotherapy, there are patients who either do not respond or have an inadequate duration of response. We previously showed that tumours from chemoresistant patients have an immunosuppressed pre-existing tumour immune microenvironment with decreased expression of Type I Interferon (IFN1) genes.

Methods

Efficacy of a ‘STimulator of INterferon Genes’ agonist was evaluated in combination with carboplatin chemotherapy and PD-1 immune checkpoint blockade therapy in the ID8-Trp53−/− immunocompetent murine model of HGSC.

Results

Treatment with STING agonist led to decreased ascites accumulation and decreased tumour burden. Survival of mice treated with a combination of carboplatin, STING agonist and anti-PD-1 antibody was the longest. Tumour immune transcriptomic profiling revealed higher IFN response, antigen presentation and MHC II genes in tumours from STING agonist-treated mice compared to vehicle controls. Flow cytometry analysis revealed significantly higher intra-tumoural PD-1+ and CD69+CD62L, CD8+ T cells in STING agonist-treated mice.

Conclusions

These findings will enable rational design of clinical trials aimed at combinatorial approaches to improve chemotherapy response and survival in HGSC patients.

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Additional information

Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License.

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Acknowledgements

The authors would like to thank Dr. Iain Mcneish (Imperial College, London, UK) for generously providing us the mouse ID8-Trp53−/− cell line. We thank Brooke Snetsinger for help with NanoString platform-based experiments and Gillian Reid-Schachter for help with images for NanoString results. This study was supported by the Tupper fund,Nancy Sutherland Ovarian cancer for Promotion of Knowledge in Ovarian Cancer and the Canadian Institutes of Health Research, funding support to M.K.

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Affiliations

  1. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    • Abdi Ghaffari
    • , Kasra Khalaj
    • , Natasha Vitkin
    •  & Madhuri Koti
  2. Department of Obstetrics and Gynecology, Kingston Health Sciences Center, Queen’s University, Kingston, ON, Canada

    • Nichole Peterson
    • , Julie-Ann Francis
    •  & Madhuri Koti
  3. Department of Oncology, Kingston Health Sciences Center, Queen’s University, Kingston, ON, Canada

    • Andrew Robinson
  4. Cancer Biology and Genetics, Queen’s Cancer Research Institute, Queen’s University, Kingston, ON, Canada

    • Madhuri Koti

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Contributions

Conception and design: M. Koti, A. Robinson, J.A. Francis. Manuscript writing and data analysis, A. Ghaffari, K. Khalaj and M. Koti. In vivo and in vitro experiments: A. Ghaffari, N. Peterson, K. Khalaj and N. Vitkin.

Competing interests

The authors declare no competing interests.

Note

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Corresponding author

Correspondence to Madhuri Koti.

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DOI

https://doi.org/10.1038/s41416-018-0188-5