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Tumor-Targeted Chemoimmunotherapy with Immune-Checkpoint Blockade for Enhanced Anti-Melanoma Efficacy

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ABSTRACT

Chemoimmunotherapy with chemotherapeutics and immunoadjuvant inhibits tumor growth by activating cytotoxic T cells. However, this process also upregulates the expression of PD-1/PD-L1 and consequently leads to immune suppression. To maximize the anti-tumor immune responses and alleviate immunosuppression, PD-L1 antibody was combined with paclitaxel (PTX) and the immunoadjuvant α-galactosylceramide (αGC), which were coencapsulated into pH-sensitive TH peptide-modified liposomes (PTX/αGC/TH-Lip) to treat melanoma and lung metastasis. Compared to treatment with PD-L1 antibody or PTX/αGC/TH-Lip alone, the combination of PD-L1 antibody and PTX/αGC/TH-Lip further elevated the tumor-specific cytotoxic T cell responses and promoted apoptosis in tumor cells, leading to enhanced anti-tumor and anti-metastatic effects. In adoptive therapy, PD-L1 antibody further alleviated immunosuppression and enhanced the anti-tumor effect of CD8+ T cells. The combination of PD-L1 antibody and chemoimmunotherapy PTX/αGC/TH-Lip provides a promising strategy for enhancing treatment for melanoma and lung metastasis.

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References

  1. Barker HE, Paget JTE, Khan AA, Harrington KJ. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer. 2015;15:409–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Cook AM, Lesterhuis WJ, Nowak AK, Lake RA. Chemotherapy and immunotherapy: map** the road ahead. Curr Opin Immunol. 2016;39:23–9.

    CAS  PubMed  Google Scholar 

  3. Kepp O, Senovilla L, Vitale I, Vacchelli E, Adjemian S, Agostinis P, et al. Consensus guidelines for the detection of immunogenic cell death. OncoImmunology. 2014;3(9):e955691.

    PubMed  PubMed Central  Google Scholar 

  4. Steinhagen F, Kinjo T, Bode C, Klinman DM. TLR-based immune adjuvants. Vaccine. 2011;29(17):3341–55.

    CAS  PubMed  Google Scholar 

  5. Parmiani G, Castelli C, Pilla L, Santinami M, Colombo MP, Rivoltini L. Opposite immune functions of GM-CSF administered as vaccine adjuvant in cancer patients. Ann Oncol. 2007;18(2):226–32.

    CAS  PubMed  Google Scholar 

  6. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192(12):5451–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Li M, Zhao M, Fu Y, Li Y, Gong T, Zhang Z, et al. Enhanced intranasal delivery of mRNA vaccine by overcoming the nasal epithelial barrier via intra- and paracellular pathways. J Control Release. 2016;228:9–19.

    CAS  PubMed  Google Scholar 

  8. Li M, Li Y, Peng K, Wang Y, Gong T, Zhang Z, et al. Engineering intranasal mRNA vaccines to enhance lymph node trafficking and immune responses. Acta Biomater. 2017;64:237–48.

    CAS  PubMed  Google Scholar 

  9. Subrahmanyam PB, Webb TJ. Boosting the immune response: the use of iNKT cell ligands as vaccine adjuvants. Front Biol. 2012;7(5):436–44.

    CAS  PubMed Central  Google Scholar 

  10. Shi S, Zhou M, Li X, Hu M, Li C, Li M, et al. Synergistic active targeting of dually integrin αvβ3/CD44-targeted nanoparticles to B16F10 tumors located at different sites of mouse bodies. J Control Release. 2016;235:1–13.

    CAS  PubMed  Google Scholar 

  11. Yang Y, Tai X, Shi K, Shaobo R, Qiu Y, Zhang Z, et al. A new concept of enhancing immuno-chemotherapeutic effects against B16F10 tumor via systemic administration by taking advantages of the limitation of EPR effect. Theranostics. 2016;6(12):2141–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24(2):207–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Gros A, Robbins PF, Yao X, Li YF, Turcotte S, Tran E, et al. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J Clin Invest. 2014;124(5):2246–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209(6):1201–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov. 2015;14:561.

    CAS  PubMed  Google Scholar 

  16. Seung-** L, Byeong-Churl J, Soo-Woong L, Young-Il Y, Seong-Il S, Yeong-Min P, et al. Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-γ-induced upregulation of B7-H1 (CD274). FEBS Lett. 2006;580(3):755–62.

    Google Scholar 

  17. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4(127):127ra37-ra37.

  18. Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol. 2016;13:273–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. New Engl J Med. 2015;372(4):320–30.

    CAS  PubMed  Google Scholar 

  20. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. New Engl J Med. 2015;372(26):2521–32.

    CAS  PubMed  Google Scholar 

  21. Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Simon S, Labarriere N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? OncoImmunology. 2018;7(1):e1364828.

    Google Scholar 

  23. Antonia SJ, Brahmer JR, Gettinger S, Chow LQ, Juergens R, Shepherd FA, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with platinum-based doublet chemotherapy (PT-DC) in advanced non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys. 2014;90(5):–S2.

  24. Amin A, Plimack ER, Infante JR, Ernstoff MS, Rini BI, McDermott DF, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32(15_suppl):5010.

    Google Scholar 

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

  26. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467–77.

    CAS  PubMed  Google Scholar 

  27. Fujii S-I, Shimizu K, Kronenberg M, Steinman RM. Prolonged IFN-γ-producing NKT response induced with α-galactosylceramide-loaded DCs. Nat Immunol. 2002;3:–867.

  28. Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov. 2005;4:145–60.

    CAS  PubMed  Google Scholar 

  29. Chen L, Han X. Anti–PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest. 2015;125(9):3384–91.

    PubMed  PubMed Central  Google Scholar 

  30. Mellor AL, Munn DH. Ido expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4:762–74.

    CAS  PubMed  Google Scholar 

  31. Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-β induces development of the TH17 lineage. Nature. 2006;441:231–4.

    CAS  Google Scholar 

  32. Liu Y, Yu Y, Yang S, Zeng B, Zhang Z, Jiao G, et al. Regulation of arginase I activity and expression by both PD-1 and CTLA-4 on the myeloid-derived suppressor cells. Cancer Immunol Immunother. 2009;58(5):687–97.

    CAS  PubMed  Google Scholar 

  33. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207(10):2175–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Chauvin J-M, Pagliano O, Fourcade J, Sun Z, Wang H, Sander C, et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest. 2015;125(5):2046–58.

    PubMed  PubMed Central  Google Scholar 

  35. Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19(5):1225–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Chretien A-S, Le Roy A, Vey N, Prebet T, Blaise D, Fauriat C, et al. Cancer-induced alterations of NK-mediated target recognition: current and investigational pharmacological strategies aiming at restoring NK-mediated anti-tumor activity. Front Immunol. 2014;5(122).

  37. Woo S-R, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T cell function to promote tumoral immune escape. Cancer Res. 2012;72(4):917–27.

    CAS  PubMed  Google Scholar 

  38. Wu MR, Zhang T, DeMars LR, Sentman CL. B7H6-specific chimeric antigen receptors lead to tumor elimination and host anti-tumor immunity. Gene Ther. 2015;22:675–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Mansour M, Pohajdak B, Kast WM, Fuentes-Ortega A, Korets-Smith E, Weir GM, et al. Therapy of established B16-F10 melanoma tumors by a single vaccination of CTL/T helper peptides in VacciMax®. J Transl Med. 2007;5(1):20.

    PubMed  PubMed Central  Google Scholar 

  40. Ming Y, Li Y, **ng H, Luo M, Li Z, Chen J, et al. Circulating tumor cells: from theory to nanotechnology-based detection. Front Pharmacol. 2017;8(114):35.

    PubMed  PubMed Central  Google Scholar 

  41. Krebs AM, Mitschke J, Lasierra Losada M, Schmalhofer O, Boerries M, Busch H, et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol. 2017;19:518–29.

    CAS  PubMed  Google Scholar 

  42. Chen L, Gibbons DL, Goswami S, Cortez MA, Ahn Y-H, Byers LA, et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun. 2014;5:5241.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Brahmer JR. Harnessing the immune system for the treatment of non-small-cell lung cancer. J Clin Oncol. 2013;31(8):1021–8.

    CAS  PubMed  Google Scholar 

  44. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci. 2010;107(17):7875–80.

    CAS  PubMed  Google Scholar 

  45. Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–7.

    CAS  PubMed  Google Scholar 

  46. Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov. 2012;11:763.

    CAS  PubMed  Google Scholar 

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Funding

We acknowledge the financial support of the National Natural Science Foundation of China (Nos. 81690261 and 81703450) and the Fundamental Research Funds for Central Universities (2018SCU12026, the Postdoctoral Foundation of Sichuan University).

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Authors and Affiliations

  1. Key Laboratory of Drug Targeting, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Section 3, Southern Renmin Road, Chengdu, 610041, People’s Republic of China

    Man Li, Yuting Yang, Jiaojie Wei, **ngli Cun, Qianwen Yu, **an Tang, Sheng Yin, Zhirong Zhang & Qin He

  2. Sichuan Academy of Chinese Medicine Science, Chengdu, 610041, People’s Republic of China

    Chaoqun Xu

  3. West China School of Stomotology, Sichuan University, Chengdu, 610041, People’s Republic of China

    Yingke Liu

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  1. Man Li
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ESM 1

The release profile of PTX/αGC-TH-Lip, PTX-TH-Lip and free PTX at pH 6.0 and 7.4. The serum stability of PTX/αGC-TH-Lip and PTX/αGC-PEG-Lip. Pilot study to determine the optimal interval of PD-L1 antibody and PTX/αGC-TH-Lip. Tumor volume of individual mouse treated with PTX/αGC-Lip+anti-PD-L1, PTX/αGC-Lip, anti-PD-L1 or HEPES buffer. Semiquantitative analysis of TUNEL staining. The H&E staining of major organs of tumor-bearing mice. (DOCX 2906 kb)

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Li, M., Yang, Y., Xu, C. et al. Tumor-Targeted Chemoimmunotherapy with Immune-Checkpoint Blockade for Enhanced Anti-Melanoma Efficacy. AAPS J 21, 18 (2019). https://doi.org/10.1208/s12248-018-0289-3

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