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Sequential administration of pemetrexed and cisplatin reprograms tumor immune microenvironment and potentiates PD-1/PD-L1 treatment in a lung cancer model
  1. Jinxiang Yu1,
  2. Qianyun Zhang1,
  3. Jie Li2,
  4. Zhaohui Si3,
  5. Yuanyuan Guo4,
  6. Xin Xu5,
  7. Kanjin Wu1
  1. 1Department of Pulmonary and Critical Care Medicine (PCCM) Ward Ⅱ, Cangzhou Central Hospital, Cangzhou, People's Republic of China
  2. 2Department of Pharmacy, Cangzhou Central Hospital, Cangzhou, People's Republic of China
  3. 3Department of Laboratory, Cangzhou Central Hospital, Cangzhou, People's Republic of China
  4. 4Department of Child Rehabilitation, Cangzhou Central Hospital, Cangzhou, People's Republic of China
  5. 5Department of Traditional Chinese Medicine 1, Cangzhou Central Hospital, Cangzhou, People's Republic of China
  1. Correspondence to Dr Qianyun Zhang, Department of Pulmonary and Critical Care Medicine (PCCM) Ward Ⅱ, Cangzhou Central Hospital, Cangzhou, China; zhangqianyun001{at}163.com

Abstract

This article aimed to investigate the effects of the administration method of pemetrexed and cisplatin on the efficacy and safety of treating non-small cell lung cancer (NSCLC) and the intrinsic molecular mechanism. Subcutaneous injection of A549 cells into BALB/C nude mice was used to explore the efficacy of different administration methods of pemetrexed and cisplatin in vivo. Immunogenic cell death (ICD) was evaluated by ATP secretion, ecto-CALR expression, and high mobility group protein 1 release. Western blot, qRT-PCR, and immunohistochemical staining were applied to detect the expression of apoptosis, cell cycle, and stimulator of interferon genes (STING) pathway-related markers. Immune microenvironment was evaluated by secretion of cytokines, infiltration of CD8+ T cells, and expression of programmed death molecular ligand-1 (PD-L1). Sequential treatment with pemetrexed and cisplatin inhibited A549 cell-driven tumor formation in nude mice and regulated the expression of apoptosis and cell cycle-related genes. STING pathway and ICD were further activated by sequential treatment with pemetrexed and cisplatin. This sequential administration method increased the levels of interferon β, tumor necrosis factor α, interleukin 12, and C-X-C motif chemokine ligand 10, enhanced the infiltration of CD8+ T cells, and upregulated the expression of PD-L1. Sequential administration of pemetrexed and cisplatin in the treatment of mouse NSCLC model may have a better effect than combination of drugs, providing theoretical basis and potential guidance for clinical medication.

  • biomedical research
  • lung diseases
  • interstitial

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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Footnotes

  • Contributors Concept or design: JY and QZ. Acquisition of data: JY, QZ, JL, ZS, YG, XX, and KW. Analysis or interpretation of data: JY, QZ, JL, and ZS. Guarantor: QD. Drafting of the manuscript: JY, QZ, JL, ZS, YG, XX, and KW. Critical revision of the manuscript for important intellectual content: all authors. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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