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  • Review Article
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Cancer nanomedicine for combination cancer immunotherapy

Abstract

Cancer immunotherapy is revolutionizing oncology. However, dose-limiting toxicities and low patient response rates remain major challenges in the clinic. Cancer nanomedicine in combination with immunotherapies offers the possibility to amplify antitumour immune responses and to sensitize tumours to immunotherapies in a safe and effective manner. In this Review, we discuss opportunities for combination immunotherapy based on nanoparticle platforms designed for chemotherapy, photothermal therapy, photodynamic therapy, radiotherapy and gene therapy. We highlight how nanoparticles can be used to reprogramme the immunosuppressive tumour microenvironment and to trigger systemic antitumour immunity, synergizing with immunotherapies against advanced cancer. Finally, we discuss strategies to improve tumour and immune cell targeting while minimizing toxicity and immune-related adverse events, and we explore the potential of theranostic nanoparticles for combination immunotherapy.

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Fig. 1: Potential clinical benefits of combination nano-immunotherapy.
Fig. 2: Nanomedicine approaches for combination cancer immunotherapy.
Fig. 3: Immune cells in the tumour microenvironment as potential targets for nano-immunotherapy.

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References

  1. McCarthy, E. F. The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop. J. 26, 154–158 (2006).

    Google Scholar 

  2. Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011).

    Article  CAS  Google Scholar 

  3. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  CAS  Google Scholar 

  4. Sharma, P. & Allison, J. P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015).

    Article  CAS  Google Scholar 

  5. Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).

    Article  CAS  Google Scholar 

  6. Topalian, S. L., Taube, J. M., Anders, R. A. & Pardoll, D. M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 16, 275–287 (2016).

    Article  CAS  Google Scholar 

  7. Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).

    Article  CAS  Google Scholar 

  8. Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

    Article  CAS  Google Scholar 

  9. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    Article  CAS  Google Scholar 

  10. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

    Article  CAS  Google Scholar 

  11. Friedman, C. F., Proverbs-Singh, T. A. & Postow, M. A. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol. 2, 1346–1353 (2016).

    Article  Google Scholar 

  12. Weber, J. S. et al. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 17, 943–955 (2016).

    Article  CAS  Google Scholar 

  13. Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).

    Article  CAS  Google Scholar 

  14. Shi, J., Kantoff, P. W., Wooster, R. & Farokhzad, O. C. Cancer nanomedicine: progress, challenges and opportunities. Nat. Rev. Cancer 17, 20–37 (2017).

    Article  CAS  Google Scholar 

  15. Matsumura, Y. & Maeda, H. A. New concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent Smancs. Cancer Res. 46, 6387–6392 (1986).

    CAS  Google Scholar 

  16. Peer, D. et al. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2, 751–760 (2007).

    Article  CAS  Google Scholar 

  17. Chou, L. Y. T., Ming, K. & Chan, W. C. W. Strategies for the intracellular delivery of nanoparticles. Chem. Soc. Rev. 40, 233–245 (2011).

    Article  CAS  Google Scholar 

  18. Bertrand, N., Wu, J., Xu, X., Kamaly, N. & Farokhzad, O. C. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv. Drug Deliv. Rev. 66, 2–25 (2014).

    Article  CAS  Google Scholar 

  19. Venditto, V. J. & Szoka, F. C. Jr. Cancer nanomedicines: so many papers and so few drugs! Adv. Drug Deliv. Rev. 65, 80–88 (2013).

    Article  CAS  Google Scholar 

  20. Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).

    Article  CAS  Google Scholar 

  21. Ojha, T. et al. Pharmacological and physical vessel modulation strategies to improve EPR-mediated drug targeting to tumors. Adv. Drug Deliv. Rev. 119, 44–60 (2017).

    Article  CAS  Google Scholar 

  22. Golombek, S. K. et al. Tumor targeting via EPR: strategies to enhance patient responses. Adv. Drug Deliv. Rev. 130, 17–38 (2018).

    Article  CAS  Google Scholar 

  23. Grippin, A. J., Sayour, E. J. & Mitchell, D. A. Translational nanoparticle engineering for cancer vaccines. Oncoimmunology 6, e1290036 (2017).

    Article  Google Scholar 

  24. Fan, Y. & Moon, J. J. Nanoparticle drug delivery systems designed to improve cancer vaccines and immunotherapy. Vaccines (Basel) 3, 662–685 (2015).

    Google Scholar 

  25. Lee, I.-H. et al. Targeted chemoimmunotherapy using drug-loaded aptamer–dendrimer bioconjugates. J. Control. Release 155, 435–441 (2011).

    Article  CAS  Google Scholar 

  26. Conde, J. et al. Dual targeted immunotherapy via in vivo delivery of biohybrid RNAi-peptide nanoparticles to tumour-associated macrophages and cancer cells. Adv. Funct. Mater. 25, 4183–4194 (2015).

    Article  CAS  Google Scholar 

  27. Sato, K. et al. Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy. Sci. Transl Med. 8, 352ra110 (2016).

    Article  CAS  Google Scholar 

  28. Zhen, Z. et al. Protein nanocage mediated fibroblast-activation protein targeted photoimmunotherapy to enhance cytotoxic T cell infiltration and tumor control. Nano Lett. 17, 862–869 (2017).

    Article  CAS  Google Scholar 

  29. Liu, L. et al. Combination immunotherapy of MUC1 mRNA nano-vaccine and CTLA-4 blockade effectively inhibits growth of triple negative breast cancer. Mol. Ther. 26, 45–55 (2018).

    Article  CAS  Google Scholar 

  30. Ochyl, L. J. et al. PEGylated tumor cell membrane vesicles as a new vaccine platform for cancer immunotherapy. Biomaterials 182, 157–166 (2018).

    Article  CAS  Google Scholar 

  31. Liu, Y., Hardie, J., Zhang, X. & Rotello, V. M. Effects of engineered nanoparticles on the innate immune system. Semin. Immunol. 34, 25–32 (2017).

    Article  CAS  Google Scholar 

  32. Wang, J. et al. Physical activation of innate immunity by spiky particles. Nat. Nanotechnol. 13, 1078–1086 (2018).

    Article  CAS  Google Scholar 

  33. Alshamsan, A. et al. STAT3 silencing in dendritic cells by siRNA polyplexes encapsulated in PLGA nanoparticles for the modulation of anticancer immune response. Mol. Pharm. 7, 1643–1654 (2010).

    Article  CAS  Google Scholar 

  34. Seth, A., Heo, M. B. & Lim, Y. T. Poly (gamma-glutamic acid) based combination of water-insoluble paclitaxel and TLR7 agonist for chemo-immunotherapy. Biomaterials 35, 7992–8001 (2014).

    Article  CAS  Google Scholar 

  35. Pradhan, P. et al. The effect of combined IL10 siRNA and CpG ODN as pathogen-mimicking microparticles on Th1/Th2 cytokine balance in dendritic cells and protective immunity against B cell lymphoma. Biomaterials 35, 5491–5504 (2014).

    Article  CAS  Google Scholar 

  36. Teo, P. Y. et al. Ovarian cancer immunotherapy using PD-L1 siRNA targeted delivery from folic acid-functionalized polyethylenimine: strategies to enhance T cell killing. Adv. Healthc. Mater. 4, 1180–1189 (2015).

    Article  CAS  Google Scholar 

  37. Kuai, R. et al. Dual TLR agonist nanodiscs as a strong adjuvant system for vaccines and immunotherapy. J. Control. Release 282, 131–139 (2018).

    Article  CAS  Google Scholar 

  38. Guo, L. et al. Combinatorial photothermal and immuno cancer therapy using chitosan-coated hollow copper sulfide nanoparticles. ACS Nano 8, 5670–5681 (2014).

    Article  CAS  Google Scholar 

  39. Wang, D. et al. Acid-activatable versatile micelleplexes for PD-L1 blockade-enhanced cancer photodynamic immunotherapy. Nano Lett. 16, 5503–5513 (2016).

    Article  CAS  Google Scholar 

  40. Kuai, R. et al. Elimination of established tumors with nanodisc-based combination chemoimmunotherapy. Sci. Adv. 4, eaao1736 (2018).

    Article  CAS  Google Scholar 

  41. Yang, G. et al. Smart nanoreactors for pH-responsive tumor homing, mitochondria-targeting, and enhanced photodynamic-immunotherapy of cancer. Nano Lett. 18, 2475–2484 (2018).

    Article  CAS  Google Scholar 

  42. Christian, D. A. & Hunter, C. A. Particle-mediated delivery of cytokines for immunotherapy. Immunotherapy 4, 425–441 (2012).

    Article  CAS  Google Scholar 

  43. Song, Q. et al. Tumor microenvironment responsive nanogel for the combinatorial antitumor effect of chemotherapy and immunotherapy. Nano Lett. 17, 6366–6375 (2017).

    Article  CAS  Google Scholar 

  44. Kong, M. et al. Biodegradable hollow mesoporous silica nanoparticles for regulating tumor microenvironment and enhancing antitumor efficiency. Theranostics 7, 3276–3292 (2017).

    Article  CAS  Google Scholar 

  45. Nam, J. et al. Surface engineering of inorganic nanoparticles for imaging and therapy. Adv. Drug Deliv. Rev. 65, 622–648 (2013).

    Article  CAS  Google Scholar 

  46. Retif, P. et al. Nanoparticles for radiation therapy enhancement: the key parameters. Theranostics 5, 1030–1044 (2015).

    Article  CAS  Google Scholar 

  47. Bao, Z., Liu, X., Liu, Y., Liu, H. & Zhao, K. Near-infrared light-responsive inorganic nanomaterials for photothermal therapy. Asian J. Pharm. Sci. 11, 349–364 (2016).

    Article  Google Scholar 

  48. Lux, F. et al. Gadolinium-based nanoparticles for theranostic MRI-radiosensitization. Nanomedicine 10, 1801–1815 (2015).

    Article  CAS  Google Scholar 

  49. Meir, R. et al. Nanomedicine for cancer immunotherapy: tracking cancer-specific T-cells in vivo with gold nanoparticles and CT imaging. ACS Nano 9, 6363–6372 (2015).

    Article  CAS  Google Scholar 

  50. Ngwa, W. et al. Targeted radiotherapy with gold nanoparticles: current status and future perspectives. Nanomedicine 9, 1063–1082 (2014).

    Article  CAS  Google Scholar 

  51. Bear, A. S. et al. Elimination of metastatic melanoma using gold nanoshell-enabled photothermal therapy and adoptive T Cell transfer. PLOS ONE 8, e69073 (2013).

    Article  CAS  Google Scholar 

  52. Toraya-Brown, S. et al. Local hyperthermia treatment of tumors induces CD8+ T cell-mediated resistance against distal and secondary tumors. Nanomedicine 10, 1273–1285 (2014).

    Article  CAS  Google Scholar 

  53. Nam, J. et al. Chemo-photothermal therapy combination elicits anti-tumor immunity against advanced metastatic cancer. Nat. Commun. 9, 1074 (2018).

    Article  CAS  Google Scholar 

  54. Hwang, S. et al. Gold nanoparticle-mediated photothermal therapy: current status and future perspective. Nanomedicine 9, 2003–2022 (2014).

    Article  CAS  Google Scholar 

  55. Chow, J. C. L. in Handbook of Ecomaterials (eds Torres Martínez, L. M., Kharissova, O. V. & Kharisov, B. I.) 1–21 (Springer International Publishing, 2017).

  56. Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281 (2012).

    Article  CAS  Google Scholar 

  57. Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).

    Article  CAS  Google Scholar 

  58. Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).

    Article  CAS  Google Scholar 

  59. Duan, X. et al. Photodynamic therapy mediated by nontoxic core–shell nanoparticles synergizes with immune checkpoint blockade to elicit antitumor immunity and antimetastatic effect on breast cancer. J. Am. Chem. Soc. 138, 16686–16695 (2016).

    Article  CAS  Google Scholar 

  60. Fan, Y. et al. Immunogenic cell death amplified by co-localized adjuvant delivery for cancer immunotherapy. Nano Lett. 17, 7387–7393 (2017).

    Article  CAS  Google Scholar 

  61. Lu, J. et al. Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression. Nat. Commun. 8, 1811 (2017).

    Article  CAS  Google Scholar 

  62. Lee, E. J. et al. Nanocage-therapeutics prevailing phagocytosis and immunogenic cell death awakens immunity against cancer. Adv. Mater. 30, 1705581 (2018).

    Article  CAS  Google Scholar 

  63. Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).

    Article  CAS  Google Scholar 

  64. Gubin, M. M. et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014).

    Article  CAS  Google Scholar 

  65. Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).

    Article  CAS  Google Scholar 

  66. Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G. & Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48–61 (2015).

    Article  CAS  Google Scholar 

  67. Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science 348, 124–128 (2015).

    Article  CAS  Google Scholar 

  68. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    Article  CAS  Google Scholar 

  69. Kuai, R., Ochyl, L. J., Bahjat, K. S., Schwendeman, A. & Moon, J. J. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nat. Mater. 16, 489–496 (2017).

    Article  CAS  Google Scholar 

  70. Zhu, G. et al. Albumin/vaccine nanocomplexes that assemble in vivo for combination cancer immunotherapy. Nat. Commun. 8, 1954 (2017).

    Article  CAS  Google Scholar 

  71. Kuai, R. et al. Subcutaneous nanodisc vaccination with neoantigens for combination cancer immunotherapy. Bioconjug. Chem. 29, 771–775 (2018).

    Article  CAS  Google Scholar 

  72. Borghaei, H. et al. Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) versus chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with <1% tumor PD-L1 expression: results from CheckMate 227. J. Clin. Oncol. 36, 9001–9001 (2018).

    Article  Google Scholar 

  73. Gandhi, L. et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N. Engl. J. Med. 378, 2078–2092 (2018).

    Article  CAS  Google Scholar 

  74. Paz-Ares, L. et al. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N. Engl. J. Med. 379, 2040–2051 (2018).

    Article  CAS  Google Scholar 

  75. Schmid, P. et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121 (2018).

    Article  CAS  Google Scholar 

  76. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03036098 (2019).

  77. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02807636 (2019).

  78. Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016).

    Article  CAS  Google Scholar 

  79. Lopes, G. et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥1%: open-label, phase 3 KEYNOTE-042 study [abstract]. J. Clin. Oncol. 36 (Suppl. 18), LBA4 (2018).

    Article  Google Scholar 

  80. Pfannenstiel, L. W., Lam, S. S., Emens, L. A., Jaffee, E. M. & Armstrong, T. D. Paclitaxel enhances early dendritic cell maturation and function through TLR4 signaling in mice. Cell. Immunol. 263, 79–87 (2010).

    Article  CAS  Google Scholar 

  81. Machiels, J. P. et al. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res. 61, 3689–3697 (2001).

    CAS  Google Scholar 

  82. Roy, A., Singh, M. S., Upadhyay, P. & Bhaskar, S. Nanoparticle mediated co-delivery of paclitaxel and a TLR-4 agonist results in tumor regression and enhanced immune response in the tumor microenvironment of a mouse model. Int. J. Pharm. 445, 171–180 (2013).

    Article  CAS  Google Scholar 

  83. Heo, M. B., Kim, S. Y., Yun, W. S. & Lim, Y. T. Sequential delivery of an anticancer drug and combined immunomodulatory nanoparticles for efficient chemoimmunotherapy. Int. J. Nanomed. 10, 5981–5992 (2015).

    CAS  Google Scholar 

  84. Lu, Y. et al. Exploiting in situ antigen generation and immune modulation to enhance chemotherapy response in advanced melanoma: a combination nanomedicine approach. Cancer Lett. 379, 32–38 (2016).

    Article  CAS  Google Scholar 

  85. Makkouk, A. et al. Biodegradable microparticles loaded with doxorubicin and CpG ODN for in situ immunization against cancer. AAPS J. 17, 184–193 (2015).

    Article  CAS  Google Scholar 

  86. Yin, Y. et al. Co-delivery of doxorubicin and interferon-gamma by thermosensitive nanoparticles for cancer immunochemotherapy. Mol. Pharm. 15, 4161–4172 (2018).

    Article  CAS  Google Scholar 

  87. Haque, A., Banik, N. L. & Ray, S. K. Emerging role of combination of all-trans retinoic acid and interferon-gamma as chemoimmunotherapy in the management of human glioblastoma. Neurochem. Res. 32, 2203–2209 (2007).

    Article  CAS  Google Scholar 

  88. van der Zee, J. Heating the patient: a promising approach? Ann. Oncol. 13, 1173–1184 (2002).

    Article  Google Scholar 

  89. Hildebrandt, B. et al. The cellular and molecular basis of hyperthermia. Crit. Rev. Oncol. Hematol. 43, 33–56 (2002).

    Article  Google Scholar 

  90. Evans, S. S., Repasky, E. A. & Fisher, D. T. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat. Rev. Immunol. 15, 335–349 (2015).

    Article  CAS  Google Scholar 

  91. Dickerson, E. B. et al. Gold nanorod assisted near-infrared plasmonic photothermal therapy (PPTT) of squamous cell carcinoma in mice. Cancer Lett. 269, 57–66 (2008).

    Article  CAS  Google Scholar 

  92. Weissleder, R. A clearer vision for in vivo imaging. Nat. Biotechnol. 19, 316–317 (2001).

    Article  CAS  Google Scholar 

  93. Jung, H. S. et al. Organic molecule-based photothermal agents: an expanding photothermal therapy universe. Chem. Soc. Rev. 47, 2280–2297 (2018).

    Article  CAS  Google Scholar 

  94. Chen, W. R., Singhal, A. K., Liu, H. & Nordquist, R. E. Antitumor immunity induced by laser immunotherapy and its adoptive transfer. Cancer Res. 61, 459–461 (2001).

    CAS  Google Scholar 

  95. Zhou, F. et al. InCVAX – a novel strategy for treatment of late-stage, metastatic cancers through photoimmunotherapy induced tumor-specific immunity. Cancer Lett. 359, 169–177 (2015).

    Article  CAS  Google Scholar 

  96. Wang, C. et al. Immunological responses triggered by photothermal therapy with carbon nanotubes in combination with anti-CTLA-4 therapy to inhibit cancer metastasis. Adv. Mater. 26, 8154–8162 (2014).

    Article  CAS  Google Scholar 

  97. Liu, Y. et al. Synergistic immuno photothermal nanotherapy (SYMPHONY) for the treatment of unresectable and metastatic cancers. Sci. Rep. 7, 8606 (2017).

    Article  CAS  Google Scholar 

  98. Abadeer, N. S. & Murphy, C. J. Recent progress in cancer thermal therapy using gold nanoparticles. J. Phys. Chem. C 120, 4691–4716 (2016).

    Article  CAS  Google Scholar 

  99. Chatterjee, D. K., Fong, L. S. & Zhang, Y. Nanoparticles in photodynamic therapy: an emerging paradigm. Adv. Drug Deliv. Rev. 60, 1627–1637 (2008).

    Article  CAS  Google Scholar 

  100. Korbelik, M. Induction of tumor immunity by photodynamic therapy. J. Clin. Laser Med. Surg. 14, 329–334 (1996).

    Article  CAS  Google Scholar 

  101. Castano, A. P., Mroz, P. & Hamblin, M. R. Photodynamic therapy and anti-tumour immunity. Nat. Rev. Cancer 6, 535–545 (2006).

    Article  CAS  Google Scholar 

  102. Buytaert, E., Dewaele, M. & Agostinis, P. Molecular effectors of multiple cell death pathways initiated by photodynamic therapy. Biochim. Biophys. Acta 1776, 86–107 (2007).

    CAS  Google Scholar 

  103. Skovsen, E., Snyder, J. W., Lambert, J. D. C. & Ogilby, P. R. Lifetime and diffusion of singlet oxygen in a cell. J. Phys. Chem. B 109, 8570–8573 (2005).

    Article  CAS  Google Scholar 

  104. Macdonald, I. J. & Dougherty, T. J. Basic principles of photodynamic therapy. J. Porphyr. Phthalocyanines 5, 105–129 (2001).

    Article  CAS  Google Scholar 

  105. Abrahamse, H. & Hamblin, M. R. New photosensitizers for photodynamic therapy. Biochem. J. 473, 347–364 (2016).

    Article  CAS  Google Scholar 

  106. Marrache, S., Tundup, S., Harn, D. A. & Dhar, S. Ex vivo programming of dendritic cells by mitochondria-targeted nanoparticles to produce interferon-gamma for cancer immunotherapy. ACS Nano 7, 7392–7402 (2013).

    Article  CAS  Google Scholar 

  107. Yu, X. et al. Inhibiting metastasis and preventing tumor relapse by triggering host immunity with tumor-targeted photodynamic therapy using photosensitizer-loaded functional nanographenes. ACS Nano 11, 10147–10158 (2017).

    Article  CAS  Google Scholar 

  108. Gao, L. et al. Enhanced anti-tumor efficacy through a combination of integrin αvβ6-targeted photodynamic therapy and immune checkpoint inhibition. Theranostics 6, 627–637 (2016).

    Article  CAS  Google Scholar 

  109. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392–401 (2006).

    Article  CAS  Google Scholar 

  110. Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).

    Article  CAS  Google Scholar 

  111. Castano, A. P., Mroz, P., Wu, M. X. & Hamblin, M. R. Photodynamic therapy plus low-dose cyclophosphamide generates antitumor immunity in a mouse model. Proc. Natl Acad. Sci. USA 105, 5495–5500 (2008).

    Article  CAS  Google Scholar 

  112. Mroz, P. & Hamblin, M. R. The immunosuppressive side of PDT. Photochem. Photobiol. Sci. 10, 751–758 (2011).

    Article  CAS  Google Scholar 

  113. He, C. et al. Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nat. Commun. 7, 12499 (2016).

    Article  CAS  Google Scholar 

  114. Hamblin, M. R. Upconversion in photodynamic therapy: plumbing the depths. Dalton Trans. 47, 8571–8580 (2018).

    Article  CAS  Google Scholar 

  115. Xu, J. et al. Near-infrared-triggered photodynamic therapy with multitasking upconversion nanoparticles in combination with checkpoint blockade for immunotherapy of colorectal cancer. ACS Nano 11, 4463–4474 (2017).

    Article  CAS  Google Scholar 

  116. Lu, K. et al. Chlorin-based nanoscale metal–organic framework systemically rejects colorectal cancers via synergistic photodynamic therapy and checkpoint blockade immunotherapy. J. Am. Chem. Soc. 138, 12502–12510 (2016).

    Article  CAS  Google Scholar 

  117. Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. Cancer 5, 263–274 (2005).

    Article  CAS  Google Scholar 

  118. Brown, J. M. Tumor hypoxia in cancer therapy. Methods Enzymol. 435, 295–321 (2007).

    Article  CAS  Google Scholar 

  119. Turan, I. S., Yildiz, D., Turksoy, A., Gunaydin, G. & Akkaya, E. U. A. Bifunctional photosensitizer for enhanced fractional photodynamic therapy: singlet oxygen generation in the presence and absence of light. Angew. Chem. Int. Ed. Engl. 55, 2875–2878 (2016).

    Article  CAS  Google Scholar 

  120. Chen, Z. et al. Bioinspired hybrid protein oxygen nanocarrier amplified photodynamic therapy for eliciting anti-tumor immunity and abscopal effect. ACS Nano 12, 8633–8645 (2018).

    Article  CAS  Google Scholar 

  121. Jin, C. S., Lovell, J. F., Chen, J. & Zheng, G. Ablation of hypoxic tumors with dose-equivalent photothermal, but not photodynamic, therapy using a nanostructured porphyrin assembly. ACS Nano 7, 2541–2550 (2013).

    Article  CAS  Google Scholar 

  122. Begg, A. C., Stewart, F. A. & Vens, C. Strategies to improve radiotherapy with targeted drugs. Nat. Rev. Cancer 11, 239–253 (2011).

    Article  CAS  Google Scholar 

  123. Sanche, L. Beyond radical thinking. Nature 461, 358–359 (2009).

    Article  CAS  Google Scholar 

  124. Gupta, A. et al. Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. J. Immunol. 189, 558–566 (2012).

    Article  CAS  Google Scholar 

  125. Reits, E. A. et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 203, 1259–1271 (2006).

    Article  CAS  Google Scholar 

  126. Deng, L. et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852 (2014).

    Article  CAS  Google Scholar 

  127. Burnette, B. C. et al. The efficacy of radiotherapy relies upon induction of type I interferon–dependent innate and adaptive immunity. Cancer Res. 71, 2488–2496 (2011).

    Article  CAS  Google Scholar 

  128. Demaria, S. & Formenti, S. Radiation as an immunological adjuvant: current evidence on dose and fractionation. Front. Oncol. 2, 153 (2012).

    CAS  Google Scholar 

  129. Demaria, S. et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int. J. Radiat. Oncol. Biol. Phys. 58, 862–870 (2004).

    Article  Google Scholar 

  130. Formenti, S. C. & Demaria, S. Radiation therapy to convert the tumor into an in situ vaccine. Int. J. Radiat. Oncol. Biol. Phys. 84, 879–880 (2012).

    Article  Google Scholar 

  131. Schaue, D. & McBride, W. H. Opportunities and challenges of radiotherapy for treating cancer. Nat. Rev. Clin. Oncol. 12, 527–540 (2015).

    Article  Google Scholar 

  132. Qu, Y. et al. Gamma-ray resistance of regulatory CD4+CD25+Foxp3+T cells in mice. Radiat. Res. 173, 148–157 (2010).

    Article  CAS  Google Scholar 

  133. Kachikwu, E. L. et al. Radiation enhances regulatory T cell representation. Int. J. Radiat. Oncol. Biol. Phys. 81, 1128–1135 (2011).

    Article  Google Scholar 

  134. Ngiow, S. F., McArthur, G. A. & Smyth, M. J. Radiotherapy complements immune checkpoint blockade. Cancer Cell 27, 437–438 (2015).

    Article  CAS  Google Scholar 

  135. Ngwa, W. et al. Using immunotherapy to boost the abscopal effect. Nat. Rev. Cancer 18, 313–322 (2018).

    Article  CAS  Google Scholar 

  136. Weichselbaum, R. R., Liang, H., Deng, L. & Fu, Y. X. Radiotherapy and immunotherapy: a beneficial liaison? Nat. Rev. Clin. Oncol. 14, 365–379 (2017).

    Article  CAS  Google Scholar 

  137. Patel, R., Czapar, A. E., Fiering, S., Oleinick, N. L. & Steinmetz, N. F. Radiation therapy combined with cowpea mosaic virus nanoparticle in situ vaccination initiates immune-mediated tumor regression. ACS Omega 3, 3702–3707 (2018).

    Article  CAS  Google Scholar 

  138. Demaria, S. et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 11, 728–734 (2005).

    CAS  Google Scholar 

  139. Deng, L. et al. Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 124, 687–695 (2014).

    Article  CAS  Google Scholar 

  140. Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).

    Article  CAS  Google Scholar 

  141. Kim, Y. H. et al. In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood 119, 355–363 (2012).

    Article  CAS  Google Scholar 

  142. Brody, J. D. et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J. Clin. Oncol. 28, 4324–4332 (2010).

    Article  Google Scholar 

  143. Lee, Y. et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114, 589–595 (2009).

    Article  CAS  Google Scholar 

  144. Klug, F. et al. Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24, 589–602 (2013).

    Article  CAS  Google Scholar 

  145. Tsai, C.-S. et al. Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth. Int. J. Radiat. Oncol. Biol. Phys. 68, 499–507 (2007).

    Article  CAS  Google Scholar 

  146. Dewan, M. Z. et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti–CTLA-4 antibody. Clin. Cancer Res. 15, 5379–5388 (2009).

    Article  CAS  Google Scholar 

  147. Schaue, D., Ratikan, J. A., Iwamoto, K. S. & McBride, W. H. Maximizing tumor immunity with fractionated radiation. Int. J. Radiat. Oncol. Biol. Phys. 83, 1306–1310 (2012).

    Article  CAS  Google Scholar 

  148. Kim, M. S. et al. Gold nanoparticles enhance anti-tumor effect of radiotherapy to hypoxic tumor. Radiat. Oncol. J. 34, 230–238 (2016).

    Article  Google Scholar 

  149. Liu, Y. et al. Metal-based NanoEnhancers for future radiotherapy: radiosensitizing and synergistic effects on tumor cells. Theranostics 8, 1824–1849 (2018).

    Article  CAS  Google Scholar 

  150. Song, G., Cheng, L., Chao, Y., Yang, K. & Liu, Z. Emerging nanotechnology and advanced materials for cancer radiation therapy. Adv. Mater. 29, 1700996 (2017).

    Article  CAS  Google Scholar 

  151. Xie, J. et al. Emerging strategies of nanomaterial-mediated tumor radiosensitization. Adv. Mater. 0, 1802244 (2018).

    Google Scholar 

  152. Ngwa, W., Dougan, S. & Kumar, R. Combining nanoparticle-aided radiation therapy with immunotherapy to enhance local and metastatic tumor cell kill during pancreatic cancer treatment. Int. J. Radiat. Oncol. Biol. Phys. 99, E611–E612 (2017).

    Article  Google Scholar 

  153. Lu, K. et al. Low-dose X-ray radiotherapy–radiodynamic therapy via nanoscale metal–organic frameworks enhances checkpoint blockade immunotherapy. Nat. Biomed. Eng. 2, 600–610 (2018).

    Article  Google Scholar 

  154. Lazzari, C. et al. Combination of immunotherapy with chemotherapy and radiotherapy in lung cancer: is this the beginning of the end for cancer? Ther. Adv. Med. Oncol. 10, 1758835918762094 (2018).

    Article  CAS  Google Scholar 

  155. Hwang, W. L., Pike, L. R. G., Royce, T. J., Mahal, B. A. & Loeffler, J. S. Safety of combining radiotherapy with immune-checkpoint inhibition. Nat. Rev. Clin. Oncol. 15, 477–494 (2018).

    Article  Google Scholar 

  156. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

    Article  CAS  Google Scholar 

  157. Bumcrot, D., Manoharan, M., Koteliansky, V. & Sah, D. W. RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat. Chem. Biol. 2, 711–719 (2006).

    Article  CAS  Google Scholar 

  158. Davidson, B. L. & McCray, P. B. Jr. Current prospects for RNA interference-based therapies. Nat. Rev. Genet. 12, 329–340 (2011).

    Article  CAS  Google Scholar 

  159. Huang, L. & Liu, Y. In vivo delivery of RNAi with lipid-based nanoparticles. Annu. Rev. Biomed. Eng. 13, 507–530 (2011).

    Article  CAS  Google Scholar 

  160. van der Waart, A. B. et al. siRNA silencing of PD-1 ligands on dendritic cell vaccines boosts the expansion of minor histocompatibility antigen-specific CD8+ T cells in NOD/SCID/IL2Rg(null) mice. Cancer Immunol. Immunother. 64, 645–654 (2015).

    Article  CAS  Google Scholar 

  161. Van den Bergh, J. M. et al. Monocyte-derived dendritic cells with silenced PD-1 ligands and transpresenting interleukin-15 stimulate strong tumor-reactive T cell expansion. Cancer Immunol. Res. 5, 710–715 (2017).

    Article  CAS  Google Scholar 

  162. Iwamura, K. et al. siRNA-mediated silencing of PD-1 ligands enhances tumor-specific human T cell effector functions. Gene Ther. 19, 959–966 (2012).

    Article  CAS  Google Scholar 

  163. Sheng, W. Y. & Huang, L. Cancer immunotherapy and nanomedicine. Pharm. Res. 28, 200–214 (2011).

    Article  CAS  Google Scholar 

  164. Zheng, X. et al. Silencing IDO in dendritic cells: a novel approach to enhance cancer immunotherapy in a murine breast cancer model. Int. J. Cancer 132, 967–977 (2013).

    Article  CAS  Google Scholar 

  165. Brady, M. T. et al. Down-regulation of signal transducer and activator of transcription 3 improves human acute myeloid leukemia-derived dendritic cell function. Leuk. Res. 37, 822–828 (2013).

    Article  CAS  Google Scholar 

  166. Luo, Z. et al. Nanovaccine loaded with poly I:C and STAT3 siRNA robustly elicits anti-tumor immune responses through modulating tumor-associated dendritic cells in vivo. Biomaterials 38, 50–60 (2015).

    Article  CAS  Google Scholar 

  167. Hossain, D. M. et al. TLR9-targeted STAT3 silencing abrogates immunosuppressive activity of myeloid-derived suppressor cells from prostate cancer patients. Clin. Cancer Res. 21, 3771–3782 (2015).

    Article  CAS  Google Scholar 

  168. Marine, J. C. et al. SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98, 609–616 (1999).

    Article  CAS  Google Scholar 

  169. Kubo, M., Hanada, T. & Yoshimura, A. Suppressors of cytokine signaling and immunity. Nat. Immunol. 4, 1169–1176 (2003).

    Article  CAS  Google Scholar 

  170. Shen, L., Evel-Kabler, K., Strube, R. & Chen, S. Y. Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity. Nat. Biotechnol. 22, 1546–1553 (2004).

    Article  CAS  Google Scholar 

  171. Heo, M. B. & Lim, Y. T. Programmed nanoparticles for combined immunomodulation, antigen presentation and tracking of immunotherapeutic cells. Biomaterials 35, 590–600 (2014).

    Article  CAS  Google Scholar 

  172. Xu, Z., Wang, Y., Zhang, L. & Huang, L. Nanoparticle-delivered transforming growth factor-beta siRNA enhances vaccination against advanced melanoma by modifying tumor microenvironment. ACS Nano 8, 3636–3645 (2014).

    Article  CAS  Google Scholar 

  173. Ahmed, M. et al. Systemic siRNA nanoparticle-based drugs combined with radiofrequency ablation for cancer therapy. PLOS ONE 10, e0128910 (2015).

    Article  CAS  Google Scholar 

  174. Shen, L. et al. Local blockade of interleukin 10 and C-X-C motif chemokine ligand 12 with nano-delivery promotes antitumor response in murine cancers. ACS Nano 12, 9830–9841 (2018).

    Article  CAS  Google Scholar 

  175. Xian, J., Yang, H., Lin, Y. & Liu, S. Combination nonviral murine interleukin 2 and interleukin 12 gene therapy and radiotherapy for head and neck squamous cell carcinoma. Arch. Otolaryngol. Head Neck Surg. 131, 1079–1085 (2005).

    Article  Google Scholar 

  176. Duan, S. et al. Folate-modified chitosan nanoparticles coated interferon-inducible protein-10 gene enhance cytotoxic T lymphocytes’ responses to hepatocellular carcinoma. J. Biomed. Nanotechnol. 12, 700–709 (2016).

    Article  CAS  Google Scholar 

  177. Ulmer, J. B. & Geall, A. J. Recent innovations in mRNA vaccines. Curr. Opin. Immunol. 41, 18–22 (2016).

    Article  CAS  Google Scholar 

  178. Fotin-Mleczek, M. et al. Highly potent mRNA based cancer vaccines represent an attractive platform for combination therapies supporting an improved therapeutic effect. J. Gene Med. 14, 428–439 (2012).

    Article  CAS  Google Scholar 

  179. Fotin-Mleczek, M. et al. mRNA-based vaccines synergize with radiation therapy to eradicate established tumors. Radiat. Oncol. 9, 180 (2014).

    Article  CAS  Google Scholar 

  180. Siegler, E. L., Kim, Y. J. & Wang, P. Nanomedicine targeting the tumor microenvironment: therapeutic strategies to inhibit angiogenesis, remodel matrix, and modulate immune responses. J. Cell. Immunother. 2, 69–78 (2016).

    Article  Google Scholar 

  181. Shi, K., Haynes, M. & Huang, L. Nanovaccines for remodeling the suppressive tumor microenvironment: New horizons in cancer immunotherapy. Front. Chem. Sci. Eng. 11, 676–684 (2017).

    Article  CAS  Google Scholar 

  182. Marabelle, A., Tselikas, L., de Baere, T. & Houot, R. Intratumoral immunotherapy: using the tumor as the remedy. Ann. Oncol. 28, xii33–xii43 (2017).

    Article  CAS  Google Scholar 

  183. Aznar, M. A. et al. Intratumoral delivery of immunotherapy—act locally, think globally. J. Immunol. 198, 31–39 (2017).

    Article  CAS  Google Scholar 

  184. Ishihara, J. et al. Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events. Sci. Transl Med. 9, eaan0401 (2017).

    Article  CAS  Google Scholar 

  185. Raavé, R., van Kuppevelt, T. H. & Daamen, W. F. Chemotherapeutic drug delivery by tumoral extracellular matrix targeting. J. Control. Release 274, 1–8 (2018).

    Article  CAS  Google Scholar 

  186. Dai, Q. et al. Quantifying the ligand-coated nanoparticle delivery to cancer cells in solid tumors. ACS Nano 12, 8423–8435 (2018).

    Article  CAS  Google Scholar 

  187. Jiang, W. et al. Designing nanomedicine for immuno-oncology. Nat. Biomed. Eng. 1, 0029 (2017).

    Article  Google Scholar 

  188. Ordikhani, F. et al. Targeting antigen-presenting cells by anti–PD-1 nanoparticles augments antitumor immunity. JCI Insight 3, 122700 (2018).

    Article  Google Scholar 

  189. Liu, X. et al. CD47 blockade triggers T cell–mediated destruction of immunogenic tumors. Nat. Med. 21, 1209–1215 (2015).

    Article  CAS  Google Scholar 

  190. Gibney, G. T., Weiner, L. M. & Atkins, M. B. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 17, e542–e551 (2016).

    Article  CAS  Google Scholar 

  191. Zheng, Y., Tang, L., Mabardi, L., Kumari, S. & Irvine, D. Enhancing adoptive cell therapy of cancer through targeted delivery of small-molecule immunomodulators to internalizing or noninternalizing receptors. Acs Nano 11, 3089–3100 (2017).

    Article  CAS  Google Scholar 

  192. Tang, L. et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat. Biotechnol. 36, 707–716 (2018).

    Article  CAS  Google Scholar 

  193. Predina, J. et al. Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery. Proc. Natl Acad. Sci. USA 110, 1582–1583 (2013).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  195. Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008).

    Article  CAS  Google Scholar 

  196. Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J. & Allison, J. P. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies. J. Exp. Med. 206, 1717–1725 (2009).

    Article  CAS  Google Scholar 

  197. Curiel, T. J. et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat. Med. 9, 562–567 (2003).

    Article  CAS  Google Scholar 

  198. 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, 328rv324 (2016).

    Article  CAS  Google Scholar 

  199. Dong, H. et al. Tumor-associated B7-H1 promotes T cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793 (2002).

    Article  CAS  Google Scholar 

  200. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    Article  CAS  Google Scholar 

  201. Schadendorf, D. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015).

    Article  CAS  Google Scholar 

  202. Topalian, S. L. et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  Google Scholar 

  203. Garon, E. B. et al. Pembrolizumab for the treatment of non–small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

    Article  Google Scholar 

  204. Webster, R. M. The immune checkpoint inhibitors: where are we now? Nat. Rev. Drug Discov. 13, 883 (2014).

    Article  CAS  Google Scholar 

  205. Marin-Acevedo, J. A. et al. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J. Hematol. Oncol. 11, 39 (2018).

    Article  CAS  Google Scholar 

  206. Chen, Daniel, S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

    Article  CAS  Google Scholar 

  207. Zanetti, M. Tapping CD4 T cells for cancer immunotherapy: the choice of personalized genomics. J. Immunol. 194, 2049–2056 (2015).

    Article  CAS  Google Scholar 

  208. Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).

    Article  CAS  Google Scholar 

  209. Ribas, A. et al. PD-1 blockade expands intratumoral memory T cells. Cancer Immunol. Res. 4, 194–203 (2016).

    Article  CAS  Google Scholar 

  210. Takeuchi, Y. et al. Clinical response to PD-1 blockade correlates with a sub-fraction of peripheral central memory CD4+ T cells in patients with malignant melanoma. Int. Immunol. 30, 13–22 (2018).

    Article  CAS  Google Scholar 

  211. Bauer, C. A. et al. Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. J. Clin. Invest. 124, 2425–2440 (2014).

    Article  CAS  Google Scholar 

  212. Munn, D. H., Sharma, M. D., Johnson, T. S. & Rodriguez, P. I. D. O. PTEN-expressing Tregs and control of antigen-presentation in the murine tumor microenvironment. Cancer Immunol. Immunother. 66, 1049–1058 (2017).

    Article  CAS  Google Scholar 

  213. Ni, X., Langridge, T. & Duvic, M. Depletion of regulatory T cells by targeting CC chemokine receptor type 4 with mogamulizumab. Oncoimmunology 4, e1011524 (2015).

    Article  CAS  Google Scholar 

  214. Gabrilovich, D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat. Rev. Immunol. 4, 941–952 (2004).

    Article  CAS  Google Scholar 

  215. Perrot, I. et al. Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage. J. Immunol. 178, 2763–2769 (2007).

    Article  CAS  Google Scholar 

  216. Kretz-Rommel, A. et al. In vivo targeting of antigens to human dendritic cells through DC-SIGN elicits stimulatory immune responses and inhibits tumor growth in grafted mouse models. J. Immunother. 30, 715–726 (2007).

    Article  CAS  Google Scholar 

  217. Macri, C., Dumont, C., Johnston, A. P. R. & Mintern, J. D. Targeting dendritic cells: a promising strategy to improve vaccine effectiveness. Clin. Transl Immunol. 5, e66 (2016).

    Article  CAS  Google Scholar 

  218. Dahlberg, C. I. M., Sarhan, D., Chrobok, M., Duru, A. D. & Alici, E. Natural killer cell-based therapies targeting cancer: possible strategies to gain and sustain anti-tumor activity. Front.Immunol. 6, 605 (2015).

    Article  Google Scholar 

  219. Zamai, L. et al. NK cells and cancer. J. Immunol. 178, 4011–4016 (2007).

    Article  CAS  Google Scholar 

  220. Vanherberghen, B. et al. Classification of human natural killer cells based on migration behavior and cytotoxic response. Blood 121, 1326–1334 (2013).

    Article  CAS  Google Scholar 

  221. Munn, D. H. & Bronte, V. Immune suppressive mechanisms in the tumor microenvironment. Curr. Opin. Immunol. 39, 1–6 (2016).

    Article  CAS  Google Scholar 

  222. Gonda, K. et al. Myeloid-derived suppressor cells are increased and correlated with type 2 immune responses, malnutrition, inflammation, and poor prognosis in patients with breast cancer. Oncol. Lett. 14, 1766–1774 (2017).

    Article  CAS  Google Scholar 

  223. Genard, G., Lucas, S. & Michiels, C. Reprogramming of tumor-associated macrophages with anticancer therapies: radiotherapy versus chemo- and immunotherapies. Front. Immunol 8, 828 (2017).

    Article  CAS  Google Scholar 

  224. Arlauckas, S. P. et al. In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy. Sci. Transl Med. 9, eaal3604 (2017).

    Article  Google Scholar 

  225. Scodeller, P. et al. Precision targeting of tumor macrophages with a CD206 binding peptide. Sci. Rep. 7, 14655 (2017).

    Article  CAS  Google Scholar 

  226. Fujimura, T., Kambayashi, Y., Fujisawa, Y., Hidaka, T. & Aiba, S. Tumor-associated macrophages: therapeutic targets for skin cancer. Front. Oncol. 8, 3 (2018).

    Article  Google Scholar 

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Acknowledgements

This work was supported in part by the US National Institutes of Health (NIH) (R01AI127070, R01EB022563, R01CA210273, R01CA223804 and U01CA210152), the Michigan Translational Research and Commercialization (MTRAC) for Life Sciences Hub, a University of Michigan (UM) Forbes Institute for Cancer Discovery Pilot Grant and the Emerald Foundation. J.J.M. is a Young Investigator supported by the Melanoma Research Alliance (348774), the US Department of Defense (DoD) Congressionally Directed Medical Research Programs (CDMRP) Peer Reviewed Cancer Research Program (W81XWH-16-1-0369) and a US National Science Foundation (NSF) CAREER Award (1553831). C.P. acknowledges financial support from the UM TEAM Training Program (DE007057 from the US National Institute of Dental and Craniofacial Research (NIDCR)). Opinions interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the DoD.

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J.N., S.S. and J.J.M. discussed content, researched data and wrote the manuscript. K.S.P. aided in the figure design and prepared the table. W.Z. and L.D.S. contributed to the revision of the manuscript. All authors reviewed and edited the manuscript.

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Correspondence to James J. Moon.

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A patent application for nanodisc technology has been filed with J.J.M. as an inventor, and J.J.M. is a co-founder of EVOQ Therapeutics, which develops nanodisc technology for cancer immunotherapy. All other authors declare no competing interests.

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Nam, J., Son, S., Park, K. et al. Cancer nanomedicine for combination cancer immunotherapy. Nat Rev Mater 4, 398–414 (2019). https://doi.org/10.1038/s41578-019-0108-1

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