Antitumor activity of a novel small molecule TLR7 agonist via immune response induction and tumor microenvironment modulation

Oncology Reports

Volumn 35, Issue 2, 2016, Pages 793-800

  Diao, Yuwen ^a,b,c   Wang, Xiaodong ^a,b   Wan, Yanyan ^a,b   Zhong, Jingjing ^a,b   Gao, Dong ^a,b   Liu, Yu ^a,b   Gao, Ningning ^a,b   Li, Wang ^a,b   Liu, Bing ^a,b   Huang, Xinping ^a,b   Jin, Zhenchao ^a,b   Peng, Boya ^a,b   Wang, Zhulin ^a,b   Fu, Li ^a   Chen, Siping ^a   Jin, Guangyi ^a,b  

^a Shenzhen University School of Medicine   (China)

^b Shenzhen Key Laboratory of Laser Engineering   (China)

^c DALIAN MEDICAL UNIVERSITY   (China)

Author keywords

Adenine derivatives; Immunotherapy; Solid tumor; Toll like receptor 7 agonist; Tumor microenvironment

Indexed keywords

GAMMA INTERFERON; INTERLEUKIN 12; INTERLEUKIN 6; PLACEBO; SZU 101; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR AGONIST; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; ADENINE; ANTINEOPLASTIC AGENT; MEMBRANE PROTEIN; SUCCINIC ACID DERIVATIVE; SZU-101; TLR7 PROTEIN, MOUSE;

ADAPTIVE IMMUNITY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; BREAST CARCINOMA; CANCER GROWTH; CARCINOMA CELL LINE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL INFILTRATION; CELL STIMULATION; CONTROLLED STUDY; CYTOKINE RELEASE; FEMALE; FLOW CYTOMETRY; IMMUNOCOMPETENT CELL; IN VITRO STUDY; IN VIVO STUDY; INNATE IMMUNITY; MOUSE; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; TUMOR MICROENVIRONMENT; WESTERN BLOTTING; AGONISTS; ANALOGS AND DERIVATIVES; ANIMAL; BREAST TUMOR; DISEASE MODEL; DRUG EFFECTS; IMMUNOLOGY; PATHOLOGY; TUMOR ASSOCIATED LEUKOCYTE;

ADENINE; ANIMALS; ANTINEOPLASTIC AGENTS; BLOTTING, WESTERN; BREAST NEOPLASMS; DISEASE MODELS, ANIMAL; FEMALE; FLOW CYTOMETRY; LYMPHOCYTES, TUMOR-INFILTRATING; MEMBRANE GLYCOPROTEINS; MICE; SUCCINATES; TOLL-LIKE RECEPTOR 7; TUMOR MICROENVIRONMENT;

EID: 84954305243     PISSN: 1021335X     EISSN: 17912431     Source Type: Journal    
DOI: 10.3892/or.2015.4436     Document Type: Article

References (40)

1. Barton GM and Medzhitov R: Toll like receptors and their ligands. Curr Top Microbiol Immunol 270: 81-92, 2002.
2. Iwasaki A and Medzhitov R: Toll like receptor control of the adaptive immune responses. Nat Immunol 5: 987-995, 2004.
3. Gibson SJ, Lindh JM, Riter TR, Gleason RM, Rogers LM, Fuller AE, Oesterich JL, Gorden KB, Qiu X, McKane SW, et al: Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. Cell Immunol 218: 74-86, 2002.
4. van Duin D, Medzhitov R and Shaw AC: Triggering TLR signaling in vaccination. Trends Immunol 27: 49-55, 2006.
5. Paulos CM, Kaiser A, Wrzesinski C, Hinrichs CS, Cassard L, Boni A, Muranski P, Sanchez-Perez L, Palmer DC, Yu Z, et al: Toll like receptors in tumor immunotherapy. Clin Cancer Res 13: 5280-5289, 2007.
6. Adams S: Toll like receptor agonists in cancer therapy. Immunotherapy 1: 949-964, 2009.
7. Lakshminarayanan V, Thompson P, Wolfert MA, Buskas T, Bradley JM, Pathangey LB, Madsen CS, Cohen PA, Gendler SJ and Boons GJ: Immune recognition of tumor associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine. Proc Natl Acad Sci USA 109: 261-266, 2012.
8. Hurwitz AA and Watkins SK: Immune suppression in the tumor microenvironment: A role for dendritic cell mediated tolerization of T cells. Cancer Immunol Immunother 61: 289-293, 2012.
9. Cheng C, Qu QX, Shen Y, Lv YT, Zhu YB, Zhang XG and Huang JA: Overexpression of B7H4 in tumor infiltrated dendritic cells. J Immunoassay Immunochem 32: 353-364, 2011.
10. Jochems C and Schlom J: Tumor infiltrating immune cells and prognosis: The potential link between conventional cancer therapy and immunity. Exp Biol Med (Maywood) 236: 567-579, 2011.
11. Aranda F, Vacchelli E, Obrist F, Eggermont A, Galon J, Sautès Fridman C, Cremer I, Henrik Ter Meulen J, Zitvogel L, Kroemer G, et al: Trial Watch: Toll like receptor agonists in oncological indications. OncoImmunology 3: e29179, 2014.
12. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K and Akira S: Small anti viral compounds activate immune cells via the TLR7 MyD88 dependent signaling pathway. Nat Immunol 3: 196-200, 2002.
13. Lee J, Chuang TH, Redecke V, She L, Pitha PM, Carson DA, Raz E and Cottam HB: Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: Activation of Toll like receptor 7. Proc Natl Acad Sci USA 100: 6646-6651. 2003.
14. Stary G, Bangert C, Tauber M, Strohal R, Kopp T and Stingl G: Tumoricidal activity of TLR7/8 activated inflammatory dendritic cells. J Exp Med 204: 1441-1451, 2007.
15. Zhu J, He S, Du J, Wang Z, Li W, Chen X, Jiang W, Zheng D and Jin G: Local administration of a novel Toll like receptor 7 agonist in combination with doxorubicin induces durable tumouricidal effects in a murine model of T cell lymphoma. J Hematol Oncol 8: 21, 2015.
16. Zamarin D, Holmgaard RB, Subudhi SK, Park JS, Mansour M, Palese P, Merghoub T, Wolchok JD and Allison JP: Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med 6: 226ra32, 2014.
17. Stewart TJ and Smyth MJ: Improving cancer immunotherapy by targeting tumor induced immune suppression. Cancer Metastasis Rev 30: 125-140, 2011.
18. Kanzler H, Barrat FJ, Hessel EM and Coffman RL: Therapeutic targeting of innate immunity with Toll like receptor agonists and antagonists. Nat Med 13: 552-559, 2007.
19. Stojanovic A and Cerwenka A: Natural killer cells and solid tumors. J Innate Immun 3: 355-364, 2011.
20. Whiteside TL: Immune suppression in cancer: Effects on immune cells, mechanisms and future therapeutic intervention. Semin Cancer Biol 16: 3-15, 2006.
21. Marcus A, Gowen BG, Thompson TW, Iannello A, Ardolino M, Deng W, Wang L, Shifrin N and Raulet DH: Recognition of tumors by the innate immune system and natural killer cells. Adv Immunol 122: 91-128, 2014.
22. Cho D1, Shook DR, Shimasaki N, Chang YH, Fujisaki H and Campana D: Cytotoxicity of activated natural killer cells against pediatric solid tumors. Clin Cancer Res 16: 3901-3909, 2010.
23. Moreno M, Mol BM, von Mensdorff Pouilly S, Verheijen RH, von Blomberg BM, van den Eertwegh AJ, Scheper RJ and Bontkes HJ: Toll like receptor agonists and invariant natural killer T cells enhance antibody dependent cell mediated cytotoxicity (ADCC). Cancer Lett 272: 70-76, 2008.
24. Lauzon NM, Mian F, MacKenzie R and Ashkar AA: The direct effects of Toll like receptor ligands on human NK cell cytokine production and cytotoxicity. Cell Immunol 241: 102-112, 2006.
25. Vivier E, R aulet DH, Moretta A, C aligiuri M A, Z itvogel L, Lanier LL, Yokoyama WM and Ugolini S: Innate or adaptive immunity? The example of natural killer cells. Science 331: 44-49, 2011.
26. Chanmee T, Ontong P, Konno K and Itano N: Tumor associated macrophages as major players in the tumor microenvironment. Cancers (Basel) 6: 1670-1690, 2014.
27. Mosser DM and Edwards JP: Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8: 958-969, 2008.
28. Ostuni R, Kratochvill F, Murray PJ and Natoli G: Macrophages and cancer: From mechanisms to therapeutic implications. Trends Immunol 36: 229-239, 2015.
29. Lopez Castejón G, Baroja Mazo A and Pelegrín P: Novel macrophage polarization model: From gene expression to identification of new anti inflammatory molecules. Cell Mol Life Sci 68: 3095-3107, 2011.
30. Ullrich E, Ménard C, Flament C, Terme M, Mignot G, Bonmort M, Plumas J, Chaperot L, Chaput N and Zitvogel L: Dendritic cells and innate defense against tumor cells. Cytokine Growth Factor Rev 19: 79-92, 2008.
31. Singh M, Khong H, Dai Z, Huang XF, Wargo JA, Cooper ZA, Vasilakos JP, Hwu P and Overwijk WW: Effective innate and adaptive antimelanoma immunity through localized TLR7/8 activation. J Immunol 193: 4722-4731, 2014.
32. Mao Y, Keller ET, Garfield DH, Shen K and Wang J: Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev 32: 303-315, 2013.
33. Diederichsen AC, Hjelmborg J, Christensen PB, Zeuthen J and Fenger C: Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLADR expression on tumour cells. Cancer Immunol Immunother 52: 423-428, 2003.
34. Broomfield SA, van der Most RG, Prosser AC, Mahendran S, Tovey MG, Smyth MJ, Robinson BW and Currie AJ: Locally administered TLR7 agonists drive systemic antitumor immune responses that are enhanced by antiCD40 immunotherapy. J Immunol 182: 5217-5224, 2009.
35. Hiraoka K, Miyamoto M, Cho Y, Suzuoki M, Oshikiri T, Nakakubo Y, Itoh T, Ohbuchi T, Kondo S and Katoh H: Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non small cell lung carcinoma. Br J Cancer 94: 275-280, 2006.
36. Reissfelder C, Stamova S, Gossmann C, Braun M, Bonertz A, Walliczek U, Grimm M, Rahbari NN, Koch M, Saadati M, et al: Tumor specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis. J Clin Invest 125: 739-751, 2015.
37. Yamaguchi T and Sakaguchi S: Regulatory T cells in immune surveillance and treatment of cancer. Semin Cancer Biol 16: 115-123, 2006.
38. Wang C, Zhou Q, Wang X, Wu X, Chen X, Li J, Zhu Z, Liu B and Su L: The TLR7 agonist induces tumor regression both by promoting CD4+ T cells proliferation and by reversing T regulatory cell mediated suppression via dendritic cells. Oncotarget 6: 1779-1789, 2015.
39. Nelson D, Fisher S and Robinson B: The 'Trojan Horse' approach to tumor immunotherapy: Targeting the tumor microenvironment. J Immunol Res 2014: 789069, 2014.
40. Van der Jeught K, Bialkowski L, Daszkiewicz L, Broos K, Goyvaerts C, Renmans D, Van Lint S, Heirman C, Thielemans K and Breckpot K: Targeting the tumor microenvironment to enhance antitumor immune responses. Oncotarget 6: 1359-1381, 2015.