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Statins abrogate gemcitabine-induced PD-L1 expression in pancreatic cancer-associated fibroblasts and cancer cells with improved therapeutic outcome

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Abstract

A combination of chemotherapy with immunotherapy has been proposed to have better clinical outcomes in Pancreatic Ductal Adenocarcinoma (PDAC). On the other hand, chemotherapeutics is known to have certain unwanted effects on the tumor microenvironment that may mask the expected beneficial effects of immunotherapy. Here, we have investigated the effect of gemcitabine (GEM), on two immune checkpoint proteins (PD-L1 and PD-L2) expression in cancer associated fibroblasts (CAFs) and pancreatic cancer cells (PCCs). Findings of in vitro studies conducted by using in-culture activated mouse pancreatic stellate cells (mPSCs) and human PDAC patients derived CAFs demonstrated that GEM significantly induces PD-L1 and PD-L2 expression in these cells. Moreover, GEM induced phosphorylation of STAT1 and production of multiple known PD-L1-inducing secretory proteins including IFN-γ in CAFs. Upregulation of PD-L1 in PSCs/CAFs upon GEM treatment caused T cell inactivation and apoptosis in vitro. Importantly, Statins suppressed GEM-induced PD-L1 expression both in CAFs and PCCs while abrogating the inactivation of T-cells caused by GEM-treated PSCs/CAFs. Finally, in an immunocompetent syngeneic orthotopic mouse pancreatic tumor model, simvastatin and GEM combination therapy significantly reduced intra-tumor PD-L1 expression and noticeably reduced the overall tumor burden and metastasis incidence. Together, the findings of this study have provided experimental evidence that illustrates potential unwanted side effects of GEM that could hamper the effectiveness of this drug as mono and/or combination therapy. At the same time the findings also suggest use of statins along with GEM will help in overcoming these shortcomings and warrant further clinical investigation.

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Data availability

All the data are available in the main text and the reagents used are mentioned in the text and supplementary Material. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

A.P.Minz is a recipient of Council of Scientific and Industrial Research (CSIR) students research fellowship, Government of India. To create graphical abstract, Biorender.com was used. We are thankful to the support provided by the DBT-ILS core imaging facility and transmission electron microscopy facility. We thank Madan Mohan Mallick, Mr. Sushanta Kumar Swain and Mr. Jajati Ray for their efficient technical support.

Funding

The study is partly supported by Department of Biotechnology (DBT; BT/PR32122/MED/30/2122/2019) Government of India.

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  1. Shantibhusan Senapati

    Present address: Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, 751023, India

Authors and Affiliations

  1. Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, 751023, India

    Aliva Prity Minz, Debasish Mohapatra, Madhuri Dutta, Manisha Sethi, Deepti Parida, Amlan Priyadarshee Mohapatra, Swayambara Mishra & Salona Kar

  2. Regional Centre for Biotechnology, Faridabad, Haryana, India

    Aliva Prity Minz, Manisha Sethi, Deepti Parida, Amlan Priyadarshee Mohapatra, Swayambara Mishra & Salona Kar

  3. CV Raman Global University, Bhubaneswar, Odisha, India

    Debasish Mohapatra

  4. Department of General Surgery, All India Institute of Medical Sciences, Bhubaneswar, India

    Prakash K. Sasmal

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Contributions

AM, DM and MD performed most of the experiments. Conception, design, and development of methodology, data interpretation: SS, AM Patient tissue for CAF isolation: PKS Experiments related to animal work: SS, AM, DM, MS, DP, APM, SM Writing, review, and/or revision of the manuscript: SS, AM, DM, MD, MS, DP, APM, SM, SK, PKS Study supervision: SS.

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Correspondence to Shantibhusan Senapati.

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Minz, A.P., Mohapatra, D., Dutta, M. et al. Statins abrogate gemcitabine-induced PD-L1 expression in pancreatic cancer-associated fibroblasts and cancer cells with improved therapeutic outcome. Cancer Immunol Immunother 72, 4261–4278 (2023). https://doi.org/10.1007/s00262-023-03562-9

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