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In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy

Abstract

Cancer recurrence after surgical resection remains a significant challenge in cancer therapy. Platelets, which accumulate in wound sites and interact with circulating tumour cells (CTCs), can however trigger inflammation and repair processes in the remaining tumour microenvironment. Inspired by this intrinsic ability of platelets and the clinical success of immune checkpoint inhibitors, here we show that conjugating anti-PDL1 (engineered monoclonal antibodies against programmed-death ligand 1) to the surface of platelets can reduce post-surgical tumour recurrence and metastasis. Using mice bearing partially removed primary melanomas (B16-F10) or triple-negative breast carcinomas (4T1), we found that anti-PDL1 was effectively released on platelet activation by platelet-derived microparticles, and that the administration of platelet-bound anti-PDL1 significantly prolonged overall mouse survival after surgery by reducing the risk of cancer regrowth and metastatic spread. Our findings suggest that engineered platelets can facilitate the delivery of the immunotherapeutic anti-PDL1 to the surgical bed and target CTCs in the bloodstream, thereby potentially improving the objective response rate.

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Figure 1: In situ activation of P–aPDL1 promoted release of anti-PDL1 (aPDL1) and cytokines.
Figure 2: P–aPDL1 reduced in vivo recurrence of melanoma tumours in the surgical bed.
Figure 3: P–aPDL1 triggered a robust, T-cell-mediated anti-tumour immune response.
Figure 4: P–aPDL1 reduced metastasis and local recurrence of melanoma.
Figure 5: P–aPDL1 treatment of recurrent triple negative 4T1 tumour.

References

  1. 1

    Baker, D., Masterson, T., Pace, R., Constable, W. & Wanebo, H. The influence of the surgical wound on local tumor recurrence. Surgery 106, 525–532 (1989).

    Google Scholar 

  2. 2

    Lukianova-Hleb, E. Y. et al. Intraoperative diagnostics and elimination of residual microtumours with plasmonic nanobubbles. Nat. Nanotech. 11, 525–532 (2016).

    Article  Google Scholar 

  3. 3

    Stephan, S. B. et al. Biopolymer implants enhance the efficacy of adoptive T-cell therapy. Nat. Biotechnol. 33, 97–101 (2015).

    Article  Google Scholar 

  4. 4

    Demicheli, R., Retsky, M., Hrushesky, W., Baum, M. & Gukas, I. The effects of surgery on tumor growth: a century of investigations. Ann. Oncol. mdn386 (2008).

  5. 5

    Ceelen, W., Pattyn, P. & Mareel, M. Surgery, wound healing, and metastasis: recent insights and clinical implications. Crit. Rev. Oncol. Hematol. 89, 16–26 (2014).

    Article  Google Scholar 

  6. 6

    Klevorn, L. E. & Teague, R. M. Adapting cancer immunotherapy models for the real world. Trends Immunol. 37, 354–363 (2016).

    Article  Google Scholar 

  7. 7

    O’Sullivan, D. & Pearce, E. L. Targeting T cell metabolism for therapy. Trends Immunol. 36, 71–80 (2015).

    Article  Google Scholar 

  8. 8

    Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

    Article  Google Scholar 

  9. 9

    Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).

    Article  Google Scholar 

  10. 10

    Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    Article  Google Scholar 

  11. 11

    Wang, C., Ye, Y., Hochu, G. M., Sadeghifar, H. & Gu, Z. Enhanced cancer immunotherapy by microneedle patch-assisted delivery of anti-PD1 antibody. Nano Lett. 16, 2334–2340 (2016).

    Article  Google Scholar 

  12. 12

    Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl. Med. 8, 328rv4 (2016).

    Article  Google Scholar 

  13. 13

    Buchbinder, E. I. & Hodi, F. S. Melanoma in 2015: immune-checkpoint blockade—durable cancer control. Nat. Rev. Clin. Oncol. 13, 77–78 (2016).

    Article  Google Scholar 

  14. 14

    Smyth, E. C. & Cunningham, D. Encouraging results for PD-1 inhibition in gastric cancer. Lancet Oncol. 17, 682–683 (2016).

    Article  Google Scholar 

  15. 15

    Rosenberg, J. E. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. The Lancet 387, 1909–1920 (2016).

    Article  Google Scholar 

  16. 16

    Naidoo, J. et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann. Oncol. 26, 2375–2391 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Mellati, M. et al. Anti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care 38, e137–e138 (2015).

    Article  Google Scholar 

  18. 18

    Boutros, C. et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat. Rev. Clin. Oncol. 13, 473–486 (2016).

    Article  Google Scholar 

  19. 19

    Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    Article  Google Scholar 

  20. 20

    Chen, L. & Han, X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J. Clin. Invest. 125, 3384–3391 (2015).

    Article  Google Scholar 

  21. 21

    Weber, J. S., Kahler, K. C. & Hauschild, A. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30, 2691–2697 (2012).

    Article  Google Scholar 

  22. 22

    Woo, S. R., Corrales, L. & Gajewski, T. F. The STING pathway and the T cell-inflamed tumor microenvironment. Trends Immunol. 36, 250–256 (2015).

    Article  Google Scholar 

  23. 23

    Hegde, P. S., Karanikas, V. & Evers, S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin. Cancer Res. 22, 1865–1874 (2016).

    Article  Google Scholar 

  24. 24

    Spranger, S. et al. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl. Med. 5, 200ra116 (2013).

    Article  Google Scholar 

  25. 25

    Gajewski, T. F., Schreiber, H. & Fu, Y. X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014–1022 (2013).

    Article  Google Scholar 

  26. 26

    Fesnak, A. D., June, C. H. & Levine, B. L. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 16, 566–581 (2016).

    Article  Google Scholar 

  27. 27

    Yoo, J. W., Irvine, D. J., Discher, D. E. & Mitragotri, S. Bio-inspired, bioengineered and biomimetic drug delivery carriers. Nat. Rev. Drug Discov. 10, 521–535 (2011).

    Article  Google Scholar 

  28. 28

    Tamagawa-Mineoka, R. Important roles of platelets as immune cells in the skin. J. Dermatol. Sci. 77, 93–101 (2015).

    Article  Google Scholar 

  29. 29

    Franco, A. T., Corken, A. & Ware, J. Platelets at the interface of thrombosis, inflammation, and cancer. Blood 126, 582–588 (2015).

    Article  Google Scholar 

  30. 30

    Hu, C. M. et al. Nanoparticle biointerfacing by platelet membrane cloaking. Nature 526, 118–121 (2015).

    Article  Google Scholar 

  31. 31

    Textor, J. in Platelet-Rich Plasma (eds Lana, J. F., Santana, M. H. A., Belangero, W. D., & Luzo, A. C. M. ) 61–94 (Springer, 2014).

    Google Scholar 

  32. 32

    Harker, L. A. et al. Effects of megakaryocyte growth and development factor on platelet production, platelet life span, and platelet function in healthy human volunteers. Blood 95, 2514–2522 (2000).

    Google Scholar 

  33. 33

    Nurden, A. T., Nurden, P., Sanchez, M., Andia, I. & Anitua, E. Platelets and wound healing. Front. Biosci. 13, 3532–3548 (2008).

    Google Scholar 

  34. 34

    Gay, L. J. & Felding-Habermann, B. Contribution of platelets to tumour metastasis. Nat. Rev. Cancer 11, 123–134 (2011).

    Article  Google Scholar 

  35. 35

    Nash, G. F., Turner, L. F., Scully, M. F. & Kakkar, A. K. Platelets and cancer. Lancet Oncol. 3, 425–430 (2002).

    Article  Google Scholar 

  36. 36

    Hu, Q. et al. Anticancer platelet-mimicking nanovehicles. Adv. Mater. 27, 7043–7050 (2015).

    Article  Google Scholar 

  37. 37

    Garraud, O. Editorial: platelets as immune cells in physiology and immunopathology. Front. Immunol. 6, 1–3 (2015).

    Google Scholar 

  38. 38

    Morrell, C. N., Aggrey, A. A., Chapman, L. M. & Modjeski, K. L. Emerging roles for platelets as immune and inflammatory cells. Blood 123, 2759–2767 (2014).

    Article  Google Scholar 

  39. 39

    Semple, J. W., Italiano, J. E. & Freedman, J. Platelets and the immune continuum. Nat. Rev. Immunol. 11, 264–274 (2011).

    Article  Google Scholar 

  40. 40

    Elzey, B. D. et al. Platelet-mediated modulation of adaptive immunity: a communication link between innate and adaptive immune compartments. Immunity 19, 9–19 (2003).

    Article  Google Scholar 

  41. 41

    Seifert, L. et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 532, 245–249 (2016).

    Article  Google Scholar 

  42. 42

    Topalian, S. L., Drake, C. G. & Pardoll, D. M. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr. Opin. Immunol. 24, 207–212 (2012).

    Article  Google Scholar 

  43. 43

    Siljander, P. R. M. Platelet-derived microparticles—an updated perspective. Thromb. Res. 127, S30–S33 (2011).

    Article  Google Scholar 

  44. 44

    Li, J., Sharkey, C. C., Wun, B., Liesveld, J. L. & King, M. R. Genetic engineering of platelets to neutralize circulating tumor cells. J. Control. Release 228, 38–47 (2016).

    Article  Google Scholar 

  45. 45

    Ruggeri, Z. M. & Mendolicchio, G. L. Adhesion mechanisms in platelet function. Circ. Res. 100, 1673–1685 (2007).

    Article  Google Scholar 

  46. 46

    Mause, S. F., von Hundelshausen, P., Zernecke, A., Koenen, R. R. & Weber, C. Platelet microparticles—a transcellular delivery system for RANTES promoting monocyte recruitment on endothelium. Arterioscler. Thromb. Vasc. Biol. 25, 1512–1518 (2005).

    Article  Google Scholar 

  47. 47

    Tripathi, S. & Guleria, I. Role of PD1/PDL1 pathway, and TH17 and treg cells in maternal tolerance to the fetus. Biomed. J. 38, 25–31 (2015).

    Article  Google Scholar 

  48. 48

    Headley, M. B. et al. Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature 531, 513–517 (2016).

    Article  Google Scholar 

  49. 49

    Flaumenhaft, R. Formation and fate of platelet microparticles. Blood Cells Mol. Dis. 36, 182–187 (2006).

    Article  Google Scholar 

  50. 50

    Rand, M. L., Wang, H., Bang, K. W., Packham, M. A. & Freedman, J. Rapid clearance of procoagulant platelet-derived microparticles from the circulation of rabbits. J. Thromb. Haemost. 4, 1621–1623 (2006).

    Article  Google Scholar 

  51. 51

    Lu, Y., Aimetti, A. A., Langer, R. & Gu, Z. Bioresponsive materials. Nat. Rev. Mater. 1, 16075 (2016).

    Article  Google Scholar 

  52. 52

    Cazenave, J.-P. et al. in Platelets and Megakaryocytes: Volume 1: Functional Assays (eds Gibbins, J. M. & Mahaut-Smith, M. P. ) 13–28 (Methods In Molecular Biology Series Vol. 272, Humana, 2004).

    Google Scholar 

  53. 53

    Janowska-Wieczorek, A. et al. Platelet-derived microparticles bind to hematopoietic stem/progenitor cells and enhance their engraftment after transplantation. Blood 98, 3143–3149 (2001).

    Article  Google Scholar 

  54. 54

    Cheville, N. F. & Stasko, J. Techniques in electron microscopy of animal tissue. Vet. Pathol. 51, 28–41 (2014).

    Article  Google Scholar 

  55. 55

    Zimmerman, M., Hu, X. & Liu, K. Experimental metastasis and CTL adoptive transfer immunotherapy mouse model. J. Vis. Exp. 45, 2077 (2010).

    Google Scholar 

  56. 56

    Fischer, A. H. et al. Hematoxylin and eosin staining of tissue and cell sections. Cold Spring Harb. Protoc. 5, pdb-prot4986 (2008).

    Google Scholar 

  57. 57

    Wang, C. et al. In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy. figsharehttp://dx.doi.org/10.6084/m9.figshare.4231766 (2016).

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Acknowledgements

This work was supported by grants from the Alfred P. Sloan Foundation (Sloan Research Fellowship), NC TraCS, the National Institutes of Health (Clinical and Translational Science Award (CTSA, NIH grant 1L1TR001111) to Z.G.) and a pilot grant from the University of North Carolina (UNC) Cancer Center. We acknowledge L. Huang at UNC at Chapel Hill for providing the B16F10-Luc-GFP and 4T1-Luc-GFP cell lines.

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C.W. and Z.G. designed the project. C.W., W.S., Y.Y and Q.H. performed the experiments. All authors analysed and interpreted the data. All authors contributed to the writing of the manuscript. All authors discussed the results and implications and edited the manuscript at all stages.

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Correspondence to Zhen Gu.

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Z.G. and C.W. have a pending patent entitled ‘Platelets for delivery of cancer immunotherapeutics’ (patent number, 10620-039PV1).

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Wang, C., Sun, W., Ye, Y. et al. In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy. Nat Biomed Eng 1, 0011 (2017). https://doi.org/10.1038/s41551-016-0011

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