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Rejuvenation of tumour-specific T cells through bispecific antibodies targeting PD-L1 on dendritic cells

Nature Biomedical Engineering volume 5, pages 1261–1273 (2021)Cite this article

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Abstract

Bispecific T-cell engagers (BiTEs) preferentially targeting tumour-associated antigens and stimulating CD3-mediated signalling are being used in patients to treat acute B-cell lymphoblastic leukemia. However, the potency of BiTEs in solid tumours is limited by their short half-life and their severe toxicity at relevant therapeutic doses. Here we report the design and in vivo performance of a bispecific antibody that simultaneously targets the murine T-cell co-receptor CD3ε and the murine immune checkpoint programmed-death ligand 1 (PD-L1). In multiple syngeneic tumour models, the bispecific antibody generated higher antitumour immune responses than conventional BiTEs targeting tumour-associated antigens and CD3ε. We found that the durable antigen-specific T-cell responses resulted from the rejuvenation of CD8 T cells, owing to the blockade of PD-L1 on dendritic cells (but not on tumour cells) and co-stimulation by B7-1&2 (a peripheral membrane protein on dendritic cells). Bispecific T-cell engagers targeting dendritic cells rather than tumour cells may represent a general means of T-cell rejuvenation for durable cancer immunotherapy.

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Fig. 1: PD-L1×CD3 targets PD-L1 to activate T cells in vitro.
Fig. 2: PD-L1×CD3 generates a greater antitumour effect than combination treatment in vivo.
Fig. 3: Pre-existing CD8 T cells are sufficient for the antitumour effect of PD-L1×CD3.
Fig. 4: PD-L1 on dendritic cells is essential for the antitumour effect of PD-L1×CD3.
Fig. 5: PD-L1×CD3 reshapes a distinct immunophenotypic signature in tumour-bearing mice.
Fig. 6: Co-stimulatory signalling is required for PD-L1×CD3-mediated antitumour effects.
Fig. 7: Schematic of hypothesized working model.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw datasets generated during the study are too large to be publicly shared, but they are available for research purposes from the corresponding authors on reasonable request. Source data for the figures are available from figshare with the identifier https://doi.org/10.6084/m9.figshare.14984793.

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Acknowledgements

We thank the UT Southwestern Institutional Animal Care & Use Committee (IACUC) and the Animal Resources Center (ARC). Y.-X.F. holds the Mary Nell and Ralph B. Rogers Professorship in Immunology. This work was supported by the Cancer Prevention and Research Institute of Texas (CPRIT) grant RR150072, given to Y.-X.F., and the National Institutes of Health (NIH) grant 1U54CA244719-01, to J.Q. We also thank Y. Liang, X. Cao, Z. Ren, A. Zhang, C. Dong, Z. Liu, C. Lu and B. Moon for providing experiment materials and helpful discussions.

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Authors and Affiliations

  1. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Longchao Liu, Joonbeom Bae, Casey Moore, Eric Hsu, Chuanhui Han, Jian Qiao & Yang-Xin Fu

  2. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Jiahui Chen & Zhichen Sun

  3. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Huiyu Li

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Contributions

L.L. and Y.-X.F. designed the study and analysed the data. L.L. performed the experiments. J.C. and J.B. assisted with tumour experiments. H.L. assisted with tissue staining. Z.S. assisted with bispecific antibody purification. C.H. provided mice and reagents. L.L. and Y.-X.F. wrote the manuscript. C.M., E.H. and J.Q. revised the manuscript. J.Q. assisted with data interpretation. Y.-X.F. supervised the project.

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Correspondence to Jian Qiao or Yang-Xin Fu.

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Peer review information Nature Biomedical Engineering thanks Marion Subklewe and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 PD-L1xCD3 generates superior antitumour effects than TAA-targeting BiTE in vivo.

a-b, C57BL/6 J mice were subcutaneously inoculated with 3 × 105 MC38E5 tumor cells and treated with 0.25 mg kg−1 of bispecific antibodies twice on day 10 and 15. Tumor volume was measured twice per week (a). 60 days post treatment, tumor free mice were re-challenged with 3 × 106 tumor cells (b). c-d, C57BL/6 J mice were subcutaneously inoculated with 1 × 106 TC1E5 tumor cells and treated with 0.25 mg kg−1 of bispecific antibodies twice on day 10 and 15. Tumor volume was measured twice per week (c). 60 days post treatment, tumor free mice were re-challenged with 1 × 107 tumor cells (d). e, C57BL/6 J mice were subcutaneously inoculated with 3 × 105 B16E5 tumor cells and treated with 0.25 mg kg−1 of bispecific antibodies intraperitoneally twice on day 8 and 12. f, BALB/c mice were subcutaneously inoculated with 5 × 105 TuBoE5 tumor cells and treated with 0.25 mg kg−1 of fusion proteins intraperitoneally twice on day 10 and 14. g, C57BL/6 J mice were subcutaneously inoculated with 3 × 105 MC38E5 tumor cells and treated with 0.25 mg kg−1 of fusion proteins either intratumorally or intraperitoneally twice on day 9 and 13. Data were presented as mean ± s.e.m from a representative experiment (n = 5 (a, b, f, g), 4 (c-e) biologically independent animals) of two independent experiments. Statistical analysis was performed by two-way ANOVA with Tukey’s multiple comparisons test. ****P ≤ 0.0001.

Extended Data Fig. 2 PD-L1xCD3 targets pre-existing CD8 T cells in the tumour tissue to initiate the antitumour immune response.

a-d, C57BL/6 J mice were inoculated with 1 × 106 MC38 tumor cells and treated with PD-L1xCD3 (0.25 mg kg−1 on day 10 and 15). 200 μg of anti-CD8, anti-CD4, anti-NK1.1 or 500 μg of anti-CSF1R was administrated respectively one day before treatment initiation and then twice a week for 2 weeks. The percentage of CD8 + cells (a), CD4 + cells (b), NK1.1+ cells (c) and CD11b + F4/80+ cells (d) in the spleen were detected by flow cytometry. e, C57BL/6 J mice (n = 5 biologically independent animals) were subcutaneously inoculated with 1 × 106 MC38 tumor cells and treated with 0.25 mg kg−1 of PD-L1xCD3 either intratumorally or intraperitoneally twice on day 10 and 15. f, C57BL/6 J mice (n = 3 biological replicates) were subcutaneously inoculated with 1 × 106 MC38 tumor cells and intraperitoneally treated with 0.25 mg kg−1 of PD-L1xCD3. Concentration of fusion protein in different tissues were measured by hIgG ELISA at indicated time point. Data were shown as mean ± s.e.m from a representative experiment of two independent experiments. Statistical analysis was performed by two-way ANOVA with Tukey’s multiple comparisons test. ****P ≤ 0.0001.

Extended Data Fig. 3 Co-stimulatory signaling blockade abolished PD-L1xCD3 mediated antitumour effects and the in vitro activation of T cells by TAA-targeting BiTE.

a-b, C57BL/6 J mice were inoculated with 1 × 106 MC38 tumor cells and treated with PD-L1xCD3 (0.25 mg kg−1 on day 10 and 15), 200 μg CTLA4-Ig was administrated on day 10, 13 and 15. Experimental design (a) and tumor growth curve (b) are shown. c-e, CD8 T cells were co-cultured with either tumor cells or dendritic cells in the presence of ErbxCD3. T cell activation (c), apoptotic T cells (d), supernatant IL-2 and IFN-γ (e) were measured by flow cytometry. Data were shown as mean ± s.e.m from a representative experiment of two independent experiments (n = 5 biologically independent animals). Statistical analyses were performed by two-way ANOVA with Dunnett’s multiple comparisons test (b), two-tailed unpaired Student’s t-test (c-e). ***P ≤ 0.001, ****P ≤ 0.0001.

Extended Data Fig. 4 Correlation analysis of CD28 expression with CD80/86 expression, dendritic cell infiltration and patient survival.

TCGA database was analyzed for cumulative survival according to CD28 expression (a), correlation of CD28 level with CD80 and CD86 level (b) and correlation of CD28 level with dendritic cell infiltration (c). Skin cutaneous melanoma (SKCM), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), lung adenocarcinoma (LUAD), colon adenocarcinoma (COAD), breast invasive carcinoma (BRCA). Statistical analyses were performed by log-rank test (a), and Spearman’s rho correlation test (b-c).

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Liu, L., Chen, J., Bae, J. et al. Rejuvenation of tumour-specific T cells through bispecific antibodies targeting PD-L1 on dendritic cells. Nat Biomed Eng 5, 1261–1273 (2021). https://doi.org/10.1038/s41551-021-00800-2

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