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Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles

Oncogene volume 38, pages 2380–2393 (2019)Cite this article

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Abstract

The backbone of ovarian cancer treatment is platinum-based chemotherapy and aggressive surgical debulking. New therapeutic approaches using immunotherapy via immune checkpoint blockade, which have demonstrated clinical efficacy in other tumor types, have been less promising in ovarian cancer. To increase their clinical efficacy, checkpoint inhibitors are now being tested in clinical trials in combination with chemotherapy. Here, we evaluated the impact of cisplatin on tumor immunogenicity and its in vivo roles when used alone or in combination with anti-PD-L1, in two novel murine ovarian cancer cell models. The 2F8 and its platinum-resistant derivative 2F8cis model, display distinct inflammatory profiles and chemotherapy sensitivities, and mirror the primary and recurrent human disease, respectively. Acute and chronic exposure to cisplatin enhances tumor immunogenicity by increasing calreticulin, MHC class I, antigen presentation and T-cell infiltration. Cisplatin also upregulates PD-L1 expression in vitro and in vivo, demonstrating a dual, paradoxical immune modulatory effect and supporting the rationale for combination with immune checkpoint blockade. One of the pathways activated by cisplatin treatment is the cGAS/STING pathway. Chronic cisplatin treatment led to upregulation of cGAS and STING proteins in 2F8cis compared to parental 2F8 cells, while acute exposure to cisplatin further increases cGAS and STING levels in both 2F8 and 2F8cis cells. Overexpression of cGAS/STING modifies tumor immunogenicity by upregulating PD-L1, MHC I and calreticulin in tumor cells. Anti-PD-L1 alone in a platinum-sensitive model or with cisplatin in a platinum-resistant model increases survival. These studies have high translational potential in ovarian cancer.

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Data Availability

The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This study was partly supported by the NIH/NCI R01 CA163462, Pennsylvania Department of Health and a philanthropic donation from Mr. Matthew Fletcher Deitch.

Author information

Author notes

  1. Tianzhou Ma

    Present address: Department of Epidemiology and Biostatistics, University of Maryland School of Public Health, College Park, Pittsburgh, MD, USA

  2. These authors contributed equally: Shannon Grabosch and Mirna Bulatovic

Authors and Affiliations

  1. Magee Womens Research Institute, Pittsburgh, Pennsylvania, USA

    Shannon Grabosch, Mirna Bulatovic, Feitianzhi Zeng, Lixin Zhang, Malcolm Ross, Joan Brozick, Robert P. Edwards & Anda M. Vlad

  2. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Shannon Grabosch, Mirna Bulatovic, Feitianzhi Zeng, Lixin Zhang, Malcolm Ross, Robert P. Edwards & Anda M. Vlad

  3. Magee Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Shannon Grabosch, Malcolm Ross & Robert P. Edwards

  4. Central South University Xiangya School of Medicine, Changsha, Hunan, People’s Republic of China

    Feitianzhi Zeng

  5. Department of Biostatistics, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, USA

    Tianzhou Ma, YuSi Fang & George Tseng

  6. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Eun Kim & Andrea Gambotto

  7. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Esther Elishaev

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Correspondence to Anda M. Vlad.

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Grabosch, S., Bulatovic, M., Zeng, F. et al. Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles. Oncogene 38, 2380–2393 (2019). https://doi.org/10.1038/s41388-018-0581-9

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