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Impact of Doxorubicin and Docetaxel on Immune Checkpoint Expression in Colorectal Cancer: Insights into Chemotherapy Resistance Mechanisms

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Abstract

After chemotherapy, tumor cells tend to become more aggressive, making it challenging for natural and adaptive immune responses to fight them. This often results in recurrence and metastasis, leading to higher mortality rates. The purpose of this study is to discover the mechanisms that cause chemotherapy resistance, including altered expression of immune checkpoints, in a colorectal cancer cell line. We used conventional methods to culture the SW-1116 colorectal cancer cell line in this study. The MTT assay was used to determine the IC50 and efficacy of Docetaxel and Doxorubicin. After treatment, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to analyze PD-L1, CTLA-4, and VISTA gene expression in the SW-1116 cell line. The upregulation of VISTA expression showed a significant increase (p < 0.0001) in response to both chemotherapy agents. Moreover, the expression of CTLA-4 exhibited a remarkable level of significance (p < 0.0001), and PD-L1 expression also displayed notable significance (p < 0.0001). Chemotherapeutic agents heighten immune checkpoint gene expression, highlighting potential immune response pathway modulation.

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References

  • Alipour S et al (2024) Glyburide-treated human monocyte-derived dendritic cells loaded with insulin represent tolerogenic features with anti-inflammatory responses and modulate autologous T cell responses in vitro. Int Immunopharmacol 126:111230

    Article  CAS  PubMed  Google Scholar 

  • Black M et al (2016) Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis. Oncotarget 7(9):10557–10567

    Article  PubMed  PubMed Central  Google Scholar 

  • Blank C, Mackensen A (2007) Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother 56:739–745

    Article  PubMed  Google Scholar 

  • Chen L et al (2014) Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun 5(1):5241

    Article  CAS  PubMed  Google Scholar 

  • Concha-Benavente F et al (2016) Identification of the cell-intrinsic and-extrinsic pathways downstream of EGFR and IFNγ that induce PD-L1 expression in head and neck cancer. Can Res 76(5):1031–1043

    Article  CAS  Google Scholar 

  • Cunningham D et al (2010) Colorectal cancer. Lancet 375(9719):1030–1047

    Article  PubMed  Google Scholar 

  • Deng L et al (2014) Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Investig 124(2):687–695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Derakhshani A et al (2021) Cytotoxic T-lymphocyte antigen-4 in colorectal cancer: another therapeutic side of capecitabine. Cancers (Basel) 13(10):2414

    Article  CAS  PubMed  Google Scholar 

  • Edwardson DW, Parissenti AM, Kovala AT (2019) Chemotherapy and inflammatory cytokine signalling in cancer cells and the tumour microenvironment. Advances in Experimental Medicine and Biology 1152:173–215. In book: Breast Cancer Metastasis and Drug Resistance (pp.173–215)

  • Flavell RA et al (2010) The polarization of immune cells in the tumour environment by TGFβ. Nat Rev Immunol 10(8):554–567

    Article  CAS  PubMed  Google Scholar 

  • Ghavami S et al (2009) Apoptosis and cancer: mutations within caspase genes. J Med Genet 46(8):497–510

    Article  CAS  PubMed  Google Scholar 

  • Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family revisited. Annu Rev Immunol 23:515–548

    Article  PubMed  Google Scholar 

  • Huang KC-Y et al (2020) Decitabine augments chemotherapy-induced PD-L1 upregulation for PD-L1 blockade in colorectal cancer. Cancers 12(2):462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jabbari N et al (2020) Modulation of immune checkpoints by chemotherapy in human colorectal liver metastases. Cell Rep Med 1(9):100160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kondo Y et al (2016) Differential contribution of three immune checkpoint (VISTA, CTLA-4, PD-1) pathways to antitumor responses against squamous cell carcinoma. Oral Oncol 57:54–60

    Article  CAS  PubMed  Google Scholar 

  • Kurtova AV et al (2015) Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature 517(7533):209–213

    Article  CAS  PubMed  Google Scholar 

  • Li TT et al (2021) Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA. BMC Immunol 22(1):55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li N et al (2023) Chemotherapy induces immune checkpoint VISTA expression in tumor cells via HIF-2alpha. Biochem Pharmacol 210:115492

    Article  CAS  PubMed  Google Scholar 

  • Majidi M et al (2021a) The effects of chemotherapeutic drugs on PD-L1 gene expression in breast cancer cell lines. Med Oncol 38(12):147

    Article  CAS  PubMed  Google Scholar 

  • Majidi M et al (2021b) The effects of chemotherapeutic drugs on PD-L1 gene expression in breast cancer cell lines. Med Oncol 38:1–8

    Article  Google Scholar 

  • Mittal D et al (2014) New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape. Curr Opin Immunol 27:16–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Modest DP, Pant S, Sartore-Bianchi A (2019) Treatment sequencing in metastatic colorectal cancer. Eur J Cancer 109:70–83

    Article  CAS  PubMed  Google Scholar 

  • Morgan E et al (2023) Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut 72(2):338–344

    Article  PubMed  Google Scholar 

  • Naba NM et al (2020) Doxorubicin inhibits miR-140 expression and upregulates PD-L1 expression in HCT116 cells, opposite to its effects on MDA-MB-231 cells. Turk J Biol 44(1):15–23

    CAS  PubMed  PubMed Central  Google Scholar 

  • Salonga D et al (2000) Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 6(4):1322–1327

    CAS  PubMed  Google Scholar 

  • Shan J et al (2022) Mechanism and strategies of immunotherapy resistance in colorectal cancer. Front Immunol 13:1016646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi SJ et al (2013) B7–H1 expression is associated with poor prognosis in colorectal carcinoma and regulates the proliferation and invasion of HCT116 colorectal cancer cells. PLoS ONE 8(10):e76012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sung H et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249

    Article  PubMed  Google Scholar 

  • Van Der Kraak L et al (2016) 5-Fluorouracil upregulates cell surface B7–H1 (PD-L1) expression in gastrointestinal cancers. J Immunother Cancer 4:1–8

    Google Scholar 

  • Vermeulen L et al (2010) Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 12(5):468–476

    Article  CAS  PubMed  Google Scholar 

  • Vincent J et al (2010) 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell–dependent antitumor immunity. Can Res 70(8):3052–3061

    Article  CAS  Google Scholar 

  • Wu CW, Lui RN (2022) Early-onset colorectal cancer: current insights and future directions. World J Gastrointest Oncol 14(1):230–241

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang S et al (2021) Cancer-activated doxorubicin prodrug nanoparticles induce preferential immune response with minimal doxorubicin-related toxicity. Biomaterials 272:120791

    Article  CAS  PubMed  Google Scholar 

  • Yu M et al (2017) Tim-3 is upregulated in human colorectal carcinoma and associated with tumor progression. Mol Med Rep 15(2):689–695

    Article  CAS  PubMed  Google Scholar 

  • Zhong G et al (2018) Expression of STING and PD-L1 in colorectal cancer and their correlation with clinical prognosis. Int J Clin Exp Pathol 11(3):1256–1264

    PubMed  PubMed Central  Google Scholar 

  • Zou W, Chen L (2008) Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8(6):467–477

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We express our gratitude to the research personnel affiliated with the Immunology Research Center, Tabriz University of Medical Sciences, for their valuable support in conducting the experimental procedures.

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Authors

Contributions

HN and MAY developed the study design collaboratively and created the foundational conceptual framework, while BB and BM provided essential biological materials and reagents. During the experimentation phase, HN, ZV, and DA made contributions. The analysis of the collected data was carried out by MAY, ensuring statistical accuracy and alignment with research inquiries. The manuscript was initially drafted by KMA, FJ, and FRB. Subsequent revisions were made by MS and MA to enhance the content and coherence. The entire study was overseen and supervised by BB, who ensured comprehensive oversight.

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Correspondence to Behzad Baradaran.

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The authors have not disclosed any competing interests.

Ethical Approval

The investigation was approved by Tabriz University of Medical Science’s medical ethics committee, and the ethics Identification Number is IR.TBZMED.VCR.REC.1402.077. This research was carried out by the principles of the Helsinki Declaration.

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Ahmadpour Youshanlui, M., Nasiri, H., Valedkarimi, Z. et al. Impact of Doxorubicin and Docetaxel on Immune Checkpoint Expression in Colorectal Cancer: Insights into Chemotherapy Resistance Mechanisms. Biochem Genet (2024). https://doi.org/10.1007/s10528-024-10796-4

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