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Combined targeting of CCL7 and Flt3L to promote the expansion and infiltration of cDC1s in tumors enhances T-cell activation and anti-PD-1 therapy effectiveness in NSCLC

Cellular & Molecular Immunology volume 20, pages 850–853 (2023)Cite this article

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Immune checkpoint inhibitors (ICIs), represented by anti-PD-1/PD-L1 antibodies, have been widely applied in various cancers, and the efficacy of ICIs is closely associated with the tumor immune microenvironment (TIME) [1, 2]. We previously demonstrated that the alveolar macrophage-derived chemokine CCL7 recruited conventional type 1 dendritic cells (cDC1s) to remodel the TIME, thereby promoting the expansion of T cells to inhibit non-small cell lung cancer (NSCLC) progression in KrasLSL-G12D/+Tp53fl/fl (KP) and KrasLSL-G12D/+Lkb1fl/fl (KL) mouse models [3]. Here, we showed that the fusion protein PD-1Ab7, in which CCL7 was fused with the single-chain variable fragment region (scFv) of an anti-PD-1 antibody (PD-1Ab), exhibited antitumor activity superior to that of PD-1Ab in a manner dependent on cDC1s. In addition, Fms-like tyrosine kinase 3 ligand (Flt3L) synergized with PD-1Ab7 to inhibit NSCLC progression in both the KP and the KL mouse models. Mechanistically, Flt3L promoted the generation and proliferation of cDC1s, whereas PD-1Ab7 increased the infiltration and migration of cDC1s in the TIME to potentiate the activation and proliferation of T cells. These findings not only highlight the essential roles of the PD-1Ab-based chemokine fusion strategy in targeting cDC1s and T cells to potentiate the efficacy of ICIs for cancer prevention but also provide therapeutic lead molecules for antitumor therapy.

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Acknowledgements

We thank Dr. Shengdian Wang (Chinese Academy of Sciences) for providing reagents and members of the Zhong laboratory and the core facilities of the Medical Research Institute for providing technical help.

Funding

This study was supported by grants from the National Key Research and Development Program of China (2022YFC3401500), the Natural Science Foundation of China (31930040, 32070900, and 32270951), and the Fundamental Research Funds for the Central Universities (2042022kf1187).

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Authors and Affiliations

  1. Cancer Center, Renmin Hospital of Wuhan University, Medical Research Institute and Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, 430071, China

    Hong-Peng Dong, Zhen Tang, Peng Wang & Dandan Lin

  2. College of Life Sciences, Wuhan University, Wuhan, 430072, China

    Hong-Peng Dong, Zhen Tang, Peng Wang & Bo Zhong

  3. CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Ying Li

  4. TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China

    Bo Zhong

  5. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Qian Chu

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  1. Hong-Peng Dong
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Contributions

DL and BZ designed and supervised the study. H-PD performed the major experiments. YL carried out the PD-1Ab7 blocking and binding experiments. ZT and PW performed the bioinformatic analysis. QC provided reagents. H-PD, DL, and BZ wrote the paper with input from all other authors. All authors read and approved the final manuscript.

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Correspondence to Dandan Lin.

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The authors declare no competing interests.

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Dong, HP., Li, Y., Tang, Z. et al. Combined targeting of CCL7 and Flt3L to promote the expansion and infiltration of cDC1s in tumors enhances T-cell activation and anti-PD-1 therapy effectiveness in NSCLC. Cell Mol Immunol 20, 850–853 (2023). https://doi.org/10.1038/s41423-023-00991-5

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