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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.

Interestingly, treatment of KP mice with PD-1Ab7 (70 μg per mouse every three days for five consecutive weeks) inhibited tumor progression and prolonged survival more potently than equimolar PD-1Ab treatment (45 μg) (Fig. 1c, d). Importantly, the percentages and numbers of infiltrated CD11c+CD11b-MHC II+Xcr1+ cDC1s in the tumor-burdened lungs were significantly higher in KP mice treated with PD-1Ab7 than in those treated with PD-1Ab (Fig. 1e). The results of gene expression profiling and gene set enrichment analysis (GSEA) assays suggested that migratory and endocytic pathways were more activated in cDC1s from the tumor-burdened lungs of KP mice treated with PD-1Ab7 than in those from the tumor-burdened lungs of KP mice treated with PD-1Ab (Figs. 1f, S2a and Tables S1 and S2). A primary function of mobilized cDC1s is priming T cells for activation through antigen presentation. Consistent with this notion, the T cells in the lung-infiltrated lymphocyte (LIL) population of KP mice treated with PD-1Ab7 were more activated and proliferative than those in the LIL population of KP mice treated with PD-1Ab (Fig. S2b–d). Similarly, the percentages and numbers of IFNγ-producing T cells in the bronchial draining lymph nodes (dLNs) were significantly increased in PD-1Ab7-treated KP mice compared to PD-1Ab- or PBS-treated mice (Fig. S2e). In this context, cDC1s express high levels of MHC II and MHC I molecules and are required for priming both CD4+ and CD8+ T cells and for tumor rejection [5]. Taken together, these data demonstrate that PD-1Ab7 promotes the infiltration and mobilization of cDC1s and the activation and proliferation of T cells in the KP mouse model.

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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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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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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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