Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Feb 10;73(2):40.
doi: 10.1007/s00262-023-03582-5.

Enhanced T cell immune activity mediated by Drp1 promotes the efficacy of PD-1 inhibitors in treating lung cancer

Jietao Ma #  1 , Jun Song #  2 , Xiaofang Yi  1 , Shuling Zhang  1 , Li Sun  1 , Letian Huang  1 , Chengbo Han  3
Affiliations

Enhanced T cell immune activity mediated by Drp1 promotes the efficacy of PD-1 inhibitors in treating lung cancer

Jietao Ma et al. Cancer Immunol Immunother. .

Abstract

Background: Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission plays important roles in the activation, proliferation, and migration of T cells.

Methods: We investigated the synergistic effect of Drp1-mediated T cell antitumor activities and programmed cell death protein 1 (PD-1) blockade for treating lung cancer through in vitro co-culture experiments and an in vivo nude mouse xenograft model.

Results: High expression levels of Drp1 positively regulated T cell activation, enhanced T cell-induced suppression of lung cancer cells, promoted CD8+ T cell infiltration in the tumor and spleen, and significantly enhanced the antitumor immune response of the PD-1 inhibitor pembrolizumab. The mechanism of this synergistic antitumor effect involved the secretion of immune killing-related cytokines and the regulation of the PD-1-ERK/Drp1 pathway in T cells.

Conclusions: Our findings suggest that modifying Drp1 expression in T cells could serve as a potential therapeutic target for enhancing the antitumor immune response in future immunotherapies.

Keywords: Dynamin-related protein 1; Immunotherapy; Lung cancer; Programmed cell death protein 1; T cells.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Drp1 protein detected by western blotting assay. A CD3+ T cells sorted by immunomagnetic beads (I, experimental group; II, control group). B Western blotting assay. C Western blotting assay grayscale analysis. Abbreviations: wtT: wild-type CD3+ T cells; shDT: CD3+ T cells with Drp1 knockdown; oeDT: CD3+ T cells with Drp1 overexpression; shNT and oeNT: negative control T cells of shDT and oeDT, respectively
Fig. 2
Fig. 2
Cytokine secretion levels of T cells with different expression levels of Drp1 in the co-cultured groups Secretion of IFN-γ, granzyme B, perforin, and TNF-α (A) by T cells with different Drp1 expression levels and (B) in different co-culture groups. ***p < 0.05. Abbreviations: wtT: wild-type CD3+ T cells; shDT: CD3+ T cells with Drp1 knockdown; oeDT: CD3+ T cells with Drp1 overexpression; shNT and oeNT: negative control groups of shDT and oeDT, respectively; PD-1 mAb: programmed cell death protein 1 monoclonal antibody; PBS: phosphate-buffered saline
Fig. 3
Fig. 3
Effects of T cells with different expression levels of Drp1 combined with or without PD-1 mAb on the growth of A549 cells. A and C Measurement of CFSE fluorescence to assess the proportion of viable A549 cells. B and D Determination of CFSE-PI dual fluorescence to assess the proportion of dead A549 cells. Abbreviations: wtT: wild-type CD3+ T cells; shDT: CD3+ T cells with Drp1 knockdown; oeDT: CD3+ T cells with Drp1 overexpression; shNT and oeNT: negative control groups of shDT and oeDT, respectively; PD-1 mAb: programmed cell death protein 1 monoclonal antibody; PBS: phosphate-buffered saline
Fig. 4
Fig. 4
Effects of T cells with different expression levels of Drp1 combined with or without PD-1 mAb on epithelial-mesenchymal transition (EMT) and tumor immune escape of A549 cells. A Vimentin and B E-cadherin. C PD-L1 (immunosuppression-related protein). *p < 0.05; ns, not significant. Abbreviations: wtT: wild-type CD3+ T cells; shDT: CD3+ T cells with Drp1 knockdown; oeDT: CD3+ T cells with Drp1 overexpression; shNT and oeNT: negative control groups of T-shDrp1 and T-oeDrp1, respectively; PD-1 mAb: programmed cell death protein 1 monoclonal antibody; PBS: phosphate-buffered saline
Fig. 5
Fig. 5
Tumor growth (A) and survival curves (B) of the nude mouse xenograft models Abbreviations: C: control; wtT: wild-type CD3+ T cells; shDT: CD3+ T cells with Drp1 knockdown; oeDT: CD3+ T cells with Drp1 overexpression; shNT and oeNT: negative control groups of shDT and oeDT, respectively; PD-1 mAb: programmed cell death protein 1 monoclonal antibody
Fig. 6
Fig. 6
Expression levels of proteins and phosphorylation levels of Drp1 and ERK in co-cultured groups. A Drp1. B ERK1/2. C p-Drp1s616. D p-ERK1/2T202Y204. *p < 0.05; ns, not significant. Abbreviations: wtT: wild-type CD3+ T cells; shDT: CD3+ T cells with Drp1 knockdown; oeDT: CD3+ T cells with Drp1 overexpression; shNT and oeNT: negative control groups of shDT and oeDT, respectively; PD-1 mAb: programmed cell death protein 1 monoclonal antibody; PBS: phosphate-buffered saline
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Mencoboni M, Ceppi M, Bruzzone M, Taveggia P, Cavo A, Scordamaglia F, et al. Effectiveness and safety of immune checkpoint inhibitors for patients with advanced non small-cell lung cancer in real-world: review and meta-analysis. Cancers (Basel) 2021;13(6):1388. doi: 10.3390/cancers13061388. - DOI - PMC - PubMed
    1. Cheng Y, Zhang T, Xu Q. Therapeutic advances in non-small cell lung cancer: focus on clinical development of targeted therapy and immunotherapy. MedComm. 2020;2(4):692–729. doi: 10.1002/mco2.105. - DOI - PMC - PubMed
    1. Kraus F, Ryan MT. The constriction and scission machineries involved in mitochondrial fission. J Cell Sci. 2017;130(18):2953–2960. - PubMed
    1. Simula L, Campanella M, Campello S. Targeting Drp1 and mitochondrial fission for therapeutic immune modulation. Pharmacol Res. 2019;146:104317. doi: 10.1016/j.phrs.2019.104317. - DOI - PubMed
    1. Yu YR, Imrichova H, Wang H, Chao T, Xiao Z, Gao M, et al. Disturbed mitochondrial dynamics in CD8(+) TILs reinforce T cell exhaustion. Nat Immunol. 2020;21(12):1540–1551. doi: 10.1038/s41590-020-0793-3. - DOI - PubMed