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Cited by 24Pancreatic and Hepatic Oncology ResearchCancer Immunotherapy and BiomarkersCancer, Lipids, and Metabolism

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

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Minz, Aliva Prity, Mohapatra, Debasish, Dutta, Madhuri, Sethi, Manisha, Parida, Deepti, Mohapatra, Amlan Priyadarshee, Mishra, Swayambara, Kar, Salona +2 more·2023·Cancer Immunology, Immunotherapy
DOI 10.1007/s00262-023-03562-9PMC PMC10992415
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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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  • Gemcitabine treatment upregulates PD-L1 and PD-L2 in murine pancreatic stellate cells (mPSC) and human PDAC cancer-associated fibroblasts (CAFs).

    “Minz et al. treated cultures of murine pancreatic stellate cells (mPSC) and human PDAC cancer-associated fibroblasts (CAFs) with gemcitabine, determining the upregulation of PD-L1 and PD-L2 in these cells”

    From The antitumoral effect of statins in pancreatic ductal adenocarcinoma: a scoping review (2026) · cites this paper as Minz et al., 2023

    The Results section reports that gemcitabine increased PD-L1 in mPSCs and both PD-L1 and PD-L2 in human CAFs. It explicitly reports no change in PD-L2 in mPSCs (Fig. S6), so the claim overstates the finding for those cells. (LLM, conf=0.93)

    Experimental — accuracy not yet measured

  • In immunocompetent mice with murine pancreatic cancer, tumor weights in the simvastatin + gemcitabine group were significantly lower than in other groups.

    “The weights of the tumors in the simvastatin + gemcitabine group were significantly lower than those in the other groups”

    From The antitumoral effect of statins in pancreatic ductal adenocarcinoma: a scoping review (2026) · cites this paper as Minz et al., 2023

    The in-vivo results section says tumor size and weight showed an antitumor effect of gemcitabine plus simvastatin in the mouse model. Figure 6D reports tumor weights with **p < 0.005, but the text available in our copy does not identify which groups were compared; it therefore does not establish significantly lower weight than every other group. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • In immunocompetent mice with murine pancreatic cancer, simvastatin + gemcitabine and simvastatin alone resulted in higher CD8+ T cell infiltration and lower Treg cell infiltration in tumor tissue than control groups.

    “The tumor tissue in the simvastatin + gemcitabine and simvastatin groups showed higher CD8+ T cell infiltration and lower Treg cell infiltration than in the other groups”

    From The antitumoral effect of statins in pancreatic ductal adenocarcinoma: a scoping review (2026) · cites this paper as Minz et al., 2023

  • Simvastatin and fluvastatin downregulate PD-L1 expression in both basal and gemcitabine-treated mPSC and CAFs.

    “simvastatin and fluvastatin downregulated PD-L1 expression in both basal and gemcitabine-treated mPSC and CAFs”

    From The antitumoral effect of statins in pancreatic ductal adenocarcinoma: a scoping review (2026) · cites this paper as Minz et al., 2023

  • Simvastatin and fluvastatin downregulate PD-L2 in both basal and gemcitabine-treated CAFs.

    “Simvastatin and fluvastatin also downregulated PD-L2 in both basal and gemcitabine-treated CAFs”

    From The antitumoral effect of statins in pancreatic ductal adenocarcinoma: a scoping review (2026) · cites this paper as Minz et al., 2023

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Cited by

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Authors
Minz, A. P., Mohapatra, D., Dutta, M., Sethi, M., Parida, D., Mohapatra, A. P., Mishra, S., Kar, S., Sasmal, P. K., & Senapati, S.
Affiliations
  • Regional Centre for Biotechnology (IN)
  • Institute of Life Sciences (IN)
  • All India Institute of Medical Sciences Bhubaneswar (IN)
Corresponding author
Senapati, Shantibhusan
ORCID
Venue
Cancer Immunology, Immunotherapy
Publisher
Springer Science and Business Media LLC
Published
2023-11-05
Volume
72
Issue
12
Pages
4261-4278
ISSN
  • 0340-7004 (ISSN-L)
  • 1432-0851
DOI
10.1007/s00262-023-03562-9
PMC
PMC10992415
OpenAlex
W4388376271
Cited by
24
References
5
Citations by year
2026: 8 · 2025: 10 · 2024: 6
FWCI
2.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Immunology Immunotherapy (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Department of Biotechnology, Ministry of Science and Technology, India
  • Council of Scientific and Industrial Research, India
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
gemcitabine, statins, simvastatin, PD-L1, PD-L2, pancreatic ductal adenocarcinoma, cancer-associated fibroblasts, pancreatic stellate cells, tumor microenvironment, immune checkpoint, STAT1 phosphorylation, interferon-gamma, T cell inactivation, chemotherapy-induced immunosuppression, combination therapy, metastasis
MeSH terms
Cancer-Associated Fibroblasts, Gemcitabine, Animals, Humans, Pancreatic Neoplasms, Treatment Outcome, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Mice, Tumor Microenvironment, B7-H1 Antigen

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