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Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy

Nature Immunology volume 16, pages 850–858 (2015)Cite this article

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Abstract

The success of antitumor immune responses depends on the infiltration of solid tumors by effector T cells, a process guided by chemokines. Here we show that in vivo post-translational processing of chemokines by dipeptidylpeptidase 4 (DPP4, also known as CD26) limits lymphocyte migration to sites of inflammation and tumors. Inhibition of DPP4 enzymatic activity enhanced tumor rejection by preserving biologically active CXCL10 and increasing trafficking into the tumor by lymphocytes expressing the counter-receptor CXCR3. Furthermore, DPP4 inhibition improved adjuvant-based immunotherapy, adoptive T cell transfer and checkpoint blockade. These findings provide direct in vivo evidence for control of lymphocyte trafficking via CXCL10 cleavage and support the use of DPP4 inhibitors for stabilizing biologically active forms of chemokines as a strategy to enhance tumor immunotherapy.

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Figure 1: Inhibition of DPP4 enhances naturally occurring antitumor responses to B16F10 melanoma.
Figure 2: DPP4 diminishes CXCL10 expression and limits CXCR3-mediated antitumor immunity.
Figure 3: DPP4 inhibition enhances CXCR3-mediated immunity to CT26 tumors.
Figure 4: DPP4 mediates in vivo truncation of CXCL10.
Figure 5: Inhibition of DPP4 enhances in vivo CXCL10-mediated lymphocyte trafficking.
Figure 6: DPP4 inhibition protects adjuvant-induced CXCL10 and improves tumor immunity.
Figure 7: Combination therapy established DPP4 inhibition as a general mechanism for improving tumor immunity.

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Acknowledgements

We thank S. Amigorena, P. Bousso, S. Turley and D. DiGregorio for critical reading of the manuscript. We also thank G. Hangoc (Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA) for providing the Dpp4−/− mice and C. Reis e Sousa (Immunobiology Laboratory, The Francis Crick Institute, London, UK) for the B16F10-OVA tumor cells. We thank M.A. Nicola (Plateforme d'imagerie dynamique, Institut Pasteur, Paris, France) for providing FVB CAG-luciferase transgenic mice. We acknowledge C. Hollande, D. Duffy, A. Casrouge, V. Bondet, V. Mallet, M. Buckwalter, T. Canton, M.A. Nicola and F. Cretien for advice and support. Funding was provided by the Institut Pasteur (Pasteur-Roux post-doctoral fellowship to R.B.d.S.), the Pasteur Foundation (fellowship to M.E.L.), the Ligue Contre le Cancer (M.L.A.), the Fondation ARC pour la recherche sur le cancer (M.L.A.) and the French government's Invest in the Future Program, managed by the Agence Nationale de la Recherche (LabEx Immuno-Onco (R.B.d.S., M.E.L., N.Y., M.A.I. and M.L.A.)).

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Authors and Affiliations

  1. Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France

    Rosa Barreira da Silva, Melissa E Laird, Nader Yatim, Molly A Ingersoll & Matthew L Albert

  2. Inserm U818, Paris, France

    Rosa Barreira da Silva, Melissa E Laird, Nader Yatim, Molly A Ingersoll & Matthew L Albert

  3. Human Histopathology and Animal Models, Institut Pasteur, Paris, France

    Laurence Fiette

  4. Université Paris Descartes–Sorbonne Paris Cité, Paris, France

    Laurence Fiette

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  1. Rosa Barreira da Silva
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Contributions

R.B.d.S. and M.L.A. designed the study. R.B.d.S. and M.E.L. designed, carried out and analyzed experiments. L.F. conducted histological experiments. N.Y. and M.A.I. provided technical and intellectual assistance. R.B.d.S. and M.L.A. wrote the manuscript. M.L.A. supervised the study.

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Integrated supplementary information

Supplementary Figure 1 Expression of DPP4 in B16F10 cells and tumors.

(a) C57BL/6 splenocytes and B16F10 melanoma cells were incubated with fluorochrome-conjugated anti-mDPP4 or with an isotype control. CD8+ T cells on splenocytes were gated and shown as positive control for DPP4 expression. (b) C57BL/6 wild-type (WT) and Dpp4−/– mice were subcutaneously injected with B16F10 cells. Eight days after injection, tumor homogenates were prepared and the DPP4 concentration was determined (bars represent mean ± s.e.m.; n = 3 (WT) and 4 (Dpp4−/–) mice). (c) Dpp4−/– mice were fed with control (ctrl) or sitagliptin chow prior to subcutaneous injection of B16F10 tumor cells. Tumor volumes are shown (data represent mean ± s.e.m.; n = 5 mice per group). Significance was determined using two-way ANOVA. Data are representative of 3 (a) and 2 (b,c) independent experiments.

Supplementary Figure 2 Susceptibility of mouse chemokines to DPP4-mediated processing.

(a) WT mice fed with control (ctrl) or sitagliptin chow were subcutaneously injected with B16F10 cells. Tumors were dissected at the indicated time points after tumor cell injection, and mCCL22, mCCL2 and mVEGF expression in tumor homogenates was evaluated (data represent mean ± s.e.m.; n = 4 mice per group). (b,c) Recombinant mCXCL9 and mCXCL11 (b) and mCCL2, mCCL22, mCXCL12, mCCL3, mCCL4 and mCCL5 (c) were incubated in the absence (–) or presence (+) of recombinant DPP4 and analyzed by SELDI-TOF mass spectrometry. (d) WT mice were treated as described in a. Tumors were dissected at the indicated time points, and the number of infiltrating leukocytes was determined. Graphs represent fold change in tumor infiltrates upon sitagliptin treatment when compared with ctrl treatment (dashed line). Each circle represents a single mouse; *P < 0.05. P values were generated via Mann-Whitney test. Data are representative of 2 independent experiments (a) or are pooled from 2–3 independent experiments (d).

Supplementary Figure 3 DPP4 inhibition enhances CXCL10-mediated antitumor responses to B16F10 melanoma.

(a–d) WT (a, c and d) and Ccr5−/– (b) mice fed with ctrl or sitagliptin chow were subcutaneously injected with B16F10 cells. Mice were treated with blocking antibodies to (a) mCCR5, (c) mCXCR4 or (d) mCXCL10 and compared to their respective isotype ctrl–treated animals. Tumor volumes are shown (data represent mean ± s.e.m.; n = 12 (a), 4 (b) and 6 (c, d) mice per group, *P < 0.05). Significance was determined using two-way ANOVA. Data are from 1 experiment (c,d), are representative of 2 independent experiments (b) or are pooled from 2 independent experiments (a).

Supplementary Figure 4 DPP4 inhibition does not induce recruitment of B cells, eosinophils or regulatory T cells into CT26 tumors.

BALB/c WT mice fed with ctrl or sitagliptin chow were subcutaneously injected with CT26 cells. Tumors were dissociated on day 11, and the number of infiltrating leukocytes was analyzed. Significance was determined via Mann-Whitney test. Data are representative of 2 independent experiments.

Supplementary Figure 5 DPP4 expression modulates chemokine expression in vivo.

WT (a,d) or Dpp4−/– (c) mice fed with sitagliptin or ctrl chow were injected intravenously with 5 μg of CpG-A. Graph represents percentage of mCXCL10(1–77) among total mCXCL10 determined in plasma samples at the indicated time points (6 h after CpG injection in b). (c) Dpp4−/– mice fed with ctrl or sitagliptin chow were treated as described in a. Quantification of mCXCL10(1–77) in plasma samples is shown. (d) Expression of mCCL2, mCCL3 and mCCL22 was determined in WT mice treated as described in a. Each circle on the graphs represents a single mouse. Significance was determined using the Mann-Whitney test (*P < 0.05). Data are representative of 2 independent experiments.

Supplementary Figure 6 DPP4 inhibition induces CXCL10-mediated leukocyte trafficking in vivo.

WT mice fed with sitagliptin or ctrl chow were injected intraperitoneally with mCXCL10 or PBS (a–c, e). Cellular contents in the peritoneal cavity were analyzed 12–14 h after injection. The number (a) and CXCR3 MFI (b) on CXCR3-expressing CD4+ T cells were analyzed (*P < 0.05). (c) CXCR3 MFI of peripheral blood CXCR3+CD8+ T cells. (d) WT and Dpp4−/– mice were treated as described in a. The number of leukocytes in the peritoneal cavity was evaluated 6 h after mCXCL10 injection (*P < 0.05, **P < 0.01). (e) WT mice were treated as described in a, and the number of eosinophils and neutrophils in the peritoneal cavity was evaluated. Each circle represents one mouse; data were combined from 2 independent experiments. P values were generated via Mann-Whitney test; data are from 1 experiment (c) or are pooled from 2 (a,b,e) or 3 (d) independent experiments.

Supplementary Figure 7 DPP4 regulates the chemotactic activity of DPP4-sensitive chemokines in vivo.

WT and Dpp4−/– mice were injected via the intraperitoneal (IP) route with PBS, (a) 1 μg of mCXCL9 or (b) 1 μg of mCCL5. IP washes were collected 6 h after injection, and the number of leukocyte populations was analyzed. Fold induction of chemokine-mediated over PBS-mediated leukocyte trafficking was calculated. *P < 0.05, **P < 0.005. Each circle represents a single mouse. P values from Mann-Whitney test. Data are combined from 2 independent experiments.

Supplementary Figure 8 DPP4 inhibition does not affect thioglycollate-mediated peritonitis.

WT mice fed with sitagliptin or ctrl chow were injected intraperitoneally with thioglycollate. Cellular contents in the peritoneal cavity were analyzed 24 h after injection. (a) The gating strategy used for the identification of neutrophils, eosinophils and monocytes among peritoneal leukocytes is shown. (b,c) The cell number of infiltrating myeloid (b) and lymphoid (c) populations is indicated. P values from Mann-Whitney test. Data are combined from 2 independent experiments.

Supplementary Figure 9 DPP4 inhibition does not affect the recruitment of myeloid cells in B16F10 tumors.

WT mice fed with ctrl or sitagliptin chow were subcutaneously injected with B16F10 tumor cells. Mice were given an intratumoral injection of PBS or mCXCL10 7 d after tumor-cell implant. The number of endogenous leukocytes was analyzed 12–14 h after intratumoral injection. Each circle represents a single mouse. P values from Mann-Whitney test. Data are combined from 2 independent experiments.

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Barreira da Silva, R., Laird, M., Yatim, N. et al. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat Immunol 16, 850–858 (2015). https://doi.org/10.1038/ni.3201

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