Advertisement

Inhibitory RNA Molecules in Immunotherapy for Cancer

  • Chih-Ping Mao
  • T.-C. Wu
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 623)

Abstract

Over the past few decades, our expanding knowledge of the mammalian immune system - how it is developed, activated, and regulated - has fostered hope that it may be harnessed in the future to successfully treat human cancer. The immune system activated by cancer vaccines may have the unique ability to selectively eradicate tumor cells at multiple sites in the body without inflicting damage on normal tissue. However, progress in the development of cancer vaccines that effectively capitalize on this ability has been limited and slow. The immune system is restrained by complex, negative feedback mechanisms that evolved to protect the host against autoimmunity and may also prevent antitumor immunity. In addition, tumor cells exploit a plethora of strategies to evade detection and elimination by the immune system. For these reasons, the field of cancer immunotherapy has suffered considerable setbacks in the past and faces great challenges at the present time. Some of these challenges may be overcome through the use of RNA interference, a process by which gene expression can be efficiently and specifically “knocked down” in cells. This chapter focuses on the current status and future prospects in the application of small interfering RNA and microRNA, two main forms of RNA interference, to treat cancer by curtailing mechanisms that attenuate the host immune response.

Key words

RNA interference (RNAi) Small interfering RNA (siRNA) MicroRNA (miRNA) Cancer Tumor Immunotherapy Vaccine Dendritic cell T cell 

Notes

Acknowledgments

This review is not intended to be an encyclopedic one, and we apologize to any authors not cited. We would like to thank Ms. Archana Monie for help with preparation of the manuscript and Ms. Lucy Wangaruro for excellent secretarial support. This work is funded by the National Cancer Institute SPORE (P50CA098252) and the NCDDG program (U19 CA113341).

References

  1. 1.
    Caplen, N.J. (2004) Gene therapy progress and prospects. Downregulating gene expression: the impact of RNA interference. Gene Ther. 11, 1241–1248.CrossRefPubMedGoogle Scholar
  2. 2.
    Leung, R.K. and Whittaker, P.A. (2005) RNA interference: from gene silencing to gene-specific therapeutics. Pharmacol. Ther. 107, 222–239.CrossRefPubMedGoogle Scholar
  3. 3.
    Shankar, P., Manjunath, N. and Lieberman, J. (2005) The prospect of silencing disease using RNA interference. JAMA 293, 1367–1373.CrossRefPubMedGoogle Scholar
  4. 4.
    Pai, S.I., Lin, Y.Y., Macaes, B., Meneshian, A., Hung, C.F. and Wu, T.C. (2006) Prospects of RNA interference therapy for cancer. Gene Ther. 13, 464–477.CrossRefPubMedGoogle Scholar
  5. 5.
    Bartel, D.P. (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297.CrossRefPubMedGoogle Scholar
  6. 6.
    Lee, E.G., Boone, D.L., Chai, S., Libby, S.L., Chien, M., Lodolce, J.P. et al. (2000) Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 289, 2350–2354.CrossRefPubMedGoogle Scholar
  7. 7.
    Boone, D.L., Turer, E.E., Lee, E.G, Ahmad, R.C., Wheeler, M.T., Tsui, C. et al. (2004) The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat. Immunol. 5, 1052–1060.CrossRefPubMedGoogle Scholar
  8. 8.
    Shen, L., Evel-Kabler, K., Strube, R. and Chen, S.Y. (2004) Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity. Nat. Biotechnol. 22, 1546–1553.CrossRefPubMedGoogle Scholar
  9. 9.
    Kubo, M., Hanada, T. and Yoshimura, A. (2003) Suppressors of cytokine signaling and immunity. Nat. Immunol. 4, 1169–7116.CrossRefPubMedGoogle Scholar
  10. 10.
    Song, X.T., Evel-Kabler, K., Shen, L., Rollins, L., Huang, X.F. and Chen, S.Y. (2008) A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression. Nat. Med. 14, 258–265.CrossRefPubMedGoogle Scholar
  11. 11.
    Zhou, H., Zhang, D., Wang, Y., Dai, M., Zhang, L., Liu, W. et al. (2006) Induction of CML28-specific cytotoxic T cell responses using co-transfected dendritic cells with CML28 DNA vaccine and SOCS1 small interfering RNA expression vector. Biochem. Biophys. Res. Commun. 347, 200–207.CrossRefPubMedGoogle Scholar
  12. 12.
    Yang, R., Yang, X., Zhang, Z., Zhang, Y., Wang, S., Cai, Z. et al. (2006) Single-walled carbon nanotubes-mediated in vivo and in vitro delivery of siRNA into antigen-presenting cells. Gene Ther. 13, 1714–1723.CrossRefPubMedGoogle Scholar
  13. 13.
    Rothlin, C.V., Ghosh, S., Zuniga, E.I., Oldstone, M.B. and Lemke, G. (2007) TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131, 1124–1136.CrossRefPubMedGoogle Scholar
  14. 14.
    Lu, Q. and Lemke, G. (2001) Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science 293, 306–311.CrossRefPubMedGoogle Scholar
  15. 15.
    Wallet, M.A., Sen, P., Flores, R.R., Wang, Y., Yi, Z., Huang, Y. et al. (2008) MerTK is required for apoptotic cell-induced T cell tolerance. J. Exp. Med. 205, 219–232.CrossRefPubMedGoogle Scholar
  16. 16.
    Munn, D.H., Sharma, M.D., Lee, J.R., Jhaver, K.G., Johnson, T.S., Keskin, D.B. et al. (2002) Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297, 1867–1870.CrossRefPubMedGoogle Scholar
  17. 17.
    Munn, D.H., Sharma, M.D., Hou, D., Baban, B., Lee, J.R., Antonia, S.J. et al. (2004) Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J. Clin. Invest. 114, 280–290.PubMedGoogle Scholar
  18. 18.
    Carter, L., Fouser, L.A., Jussif, J., Fitz, L., Deng, B., Wood, C.R. et al. (2002) PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur. J. Immunol. 32, 634–643.CrossRefPubMedGoogle Scholar
  19. 19.
    Latchman, Y., Wood, C.R., Chernova, T., Chaudhary, D., Borde, M., Chernova, I. et al. (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2, 261–268.CrossRefPubMedGoogle Scholar
  20. 20.
    Brown, J.A., Dorfman, D.M., Ma, F.R., Sullivan, E.L., Munoz, O., Wood, C.R. et al. (2003) Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J. Immunol. 170, 1257–1266.PubMedGoogle Scholar
  21. 21.
    Curiel, T.J., Wei, S., Dong, H., Alvarez, X., Cheng, P., Mottram, P. et al. (2003) Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat. Med. 9, 562–567.CrossRefPubMedGoogle Scholar
  22. 22.
    Shi, L., Luo, K., Xia, D., Chen, T., Chen, G., Jiang, Y. et al. (2006) DIgR2, dendritic cell-derived immunoglobulin receptor 2, is one representative of a family of IgSF inhibitory receptors and mediates negative regulation of dendritic cell-initiated antigen-specific T-cell responses. Blood 108, 2678–2686.CrossRefPubMedGoogle Scholar
  23. 23.
    Hoyne, G.F., Le Roux, I., Corsin-Jimenez, M., Tan, K., Dunne, J., Forsyth, L.M. et al. (2000) Serrate1-induced notch signalling regulates the decision between immunity and tolerance made by peripheral CD4(+) T cells. Int. Immunol. 12, 177–185.CrossRefPubMedGoogle Scholar
  24. 24.
    Wong, K.K., Carpenter, M.J., Young, L.L., Walker, S.J., McKenzie, G., Rust, A.J. et al. (2003) Notch ligation by Delta1 inhibits peripheral immune responses to transplantation antigens by a CD8+ cell-dependent mechanism. J. Clin. Invest. 112, 1741–1750.PubMedGoogle Scholar
  25. 25.
    Amsen, D., Blander, J.M., Lee, G.R., Tanigaki, K., Honjo, T. and Flavell, R.A. (2004) Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117, 515–526.CrossRefPubMedGoogle Scholar
  26. 26.
    Stallwood, Y., Briend, E., Ray, K.M., Ward, G.A., Smith, B.J., Nye, E. et al. (2006) Small interfering RNA-mediated knockdown of notch ligands in primary CD4+ T cells and dendritic cells enhances cytokine production. J. Immunol. 177, 885–895.PubMedGoogle Scholar
  27. 27.
    Huang, B., Mao, C.P., Peng, S., Hung, C.F. and Wu, T.C. (2008) RNA interference-mediated in vivo silencing of fas ligand as a strategy for the enhancement of DNA vaccine potency. Hum. Gene Ther. 19, 763–773.CrossRefPubMedGoogle Scholar
  28. 28.
    Iellem, A., Mariani, M., Lang, R., Recalde, H., Panina-Bordignon, P., Sinigaglia, F. et al. (2001) Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J. Exp. Med. 194, 847–853.CrossRefPubMedGoogle Scholar
  29. 29.
    Baltimore, D., Boldin, M.P., O’Connell, R.M., Rao, D.S. and Taganov, K.D. (2008) MicroRNAs: new regulators of immune cell development and function. Nat. Immunol. 9, 839–845.CrossRefPubMedGoogle Scholar
  30. 30.
    Rodriguez, A., Vigorito, E., Clare, S., Warren, M.V., Couttet, P., Soond, D.R. et al. (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611.CrossRefPubMedGoogle Scholar
  31. 31.
    Thai, T.H., Calado, D.P., Casola, S., Ansel, K.M., Xiao, C., Xue, Y. et al. (2007) Regulation of the germinal center response by microRNA-155. Science 316, 604–608.CrossRefPubMedGoogle Scholar
  32. 32.
    Taganov, K.D., Boldin, M.P., Chang, K.J. and Baltimore, D. (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl. Acad. Sci. U.S.A. 103, 12481–12486.CrossRefPubMedGoogle Scholar
  33. 33.
    Liu, G., Ng, H., Akasaki, Y., Yuan, X., Ehtesham, M., Yin, D. et al. (2004) Small interference RNA modulation of IL-10 in human monocyte-derived dendritic cells enhances the Th1 response. Eur. J. Immunol. 34, 1680–1687.CrossRefPubMedGoogle Scholar
  34. 34.
    Diehl, S. and Rincon, M. (2002) The two faces of IL-6 on Th1/Th2 differentiation. Mol. Immunol. 39, 531–536.CrossRefPubMedGoogle Scholar
  35. 35.
    Ingulli, E., Mondino, A., Khoruts, A. and Jenkins, M.K. (1997) In vivo detection of dendritic cell antigen presentation to CD4(+) T cells. J. Exp. Med. 185, 2133–2141.CrossRefPubMedGoogle Scholar
  36. 36.
    Hou, W.S. and Van Parijs, L. (2004) A Bcl-2-dependent molecular timer regulates the lifespan and immunogenicity of dendritic cells. Nat. Immunol. 5, 583–589.CrossRefPubMedGoogle Scholar
  37. 37.
    Nopora, A. and Brocker, T. (2002) Bcl-2 controls dendritic cell longevity in vivo. J. Immunol. 169, 3006–3014.PubMedGoogle Scholar
  38. 38.
    Kim, T.W., Hung, C.F., Ling, M., Juang, J., He, L., Hardwick, J.M. et al. (2003) Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins. J. Clin. Invest. 112, 109–117.PubMedGoogle Scholar
  39. 39.
    Peng, S., Kim, T.W., Lee, J.H., Yang, M., He, L., Hung, C.F. et al. (2005) Vaccination with dendritic cells transfected with BAK and BAX siRNA enhances antigen-specific immune responses by prolonging dendritic cell life. Hum. Gene Ther. 16, 584–593.CrossRefPubMedGoogle Scholar
  40. 40.
    Kim, T.W., Lee, J.H., He, L., Boyd, D.A., Hardwick, J.M., Hung, C.F. et al. (2005) Modification of professional antigen-presenting cells with small interfering RNA in vivo to enhance cancer vaccine potency. Cancer Res. 65, 309–316.PubMedGoogle Scholar
  41. 41.
    Hsieh, C.L., Chen, D.S. and Hwang, L.H. (2000) Tumor-induced immunosuppression: a barrier to immunotherapy of large tumors by cytokine-secreting tumor vaccine. Hum. Gene Ther. 11, 681–692.CrossRefPubMedGoogle Scholar
  42. 42.
    Poppema, S., Potters, M., Visser, L. and van den Berg, A.M. (1998) Immune escape mechanisms in Hodgkin’s disease. Ann. Oncol. 9 Suppl 5, S21-S24.CrossRefPubMedGoogle Scholar
  43. 43.
    Scarpa, S., Coppa, A., Ragano-Caracciolo, M., Mincione, G., Giuffrida, A., Modesti, A. et al. (1996) Transforming growth factor beta regulates differentiation and proliferation of human neuroblastoma. Exp. Cell Res. 229, 147–154.CrossRefPubMedGoogle Scholar
  44. 44.
    Jayaraman, L. and Massague, J. (2000) Distinct oligomeric states of SMAD proteins in the transforming growth factor-beta pathway. J. Biol. Chem. 275, 40710–40717.CrossRefPubMedGoogle Scholar
  45. 45.
    Massague, J. (1998) TGF-beta signal transduction. Annu. Rev. Biochem. 67, 753–791.CrossRefPubMedGoogle Scholar
  46. 46.
    Depoortere, F., Pirson, I., Bartek, J., Dumont, J.E. and Roger, P.P. (2000) Transforming growth factor beta(1) selectively inhibits the cyclic AMP-dependent proliferation of primary thyroid epithelial cells by preventing the association of cyclin D3-cdk4 with nuclear p27(kip1). Mol. Biol. Cell 11, 1061–1076.PubMedGoogle Scholar
  47. 47.
    Sandhu, C., Garbe, J., Bhattacharya, N., Bhattacharya, N., Daksis, J., Pan, C.H. et al. (1997) Transforming growth factor beta stabilizes p15INK4B protein, increases p15INK4B-cdk4 complexes, and inhibits cyclin D1-cdk4 association in human mammary epithelial cells. Mol. Cell Biol. 17, 2458–2467.PubMedGoogle Scholar
  48. 48.
    Fargeas, C., Wu, C.Y., Nakajima, T., Cox, D., Nutman, T. and Delespesse, G. (1992) Differential effect of transforming growth factor beta on the synthesis of Th1- and Th2-like lymphokines by human T lymphocytes. Eur. J. Immunol. 22, 2173–2176.CrossRefPubMedGoogle Scholar
  49. 49.
    Palladino, M.A., Morris, R.E., Starnes, H.F. and Levinson, A.D. (1990) The transforming growth factor-betas. A new family of immunoregulatory molecules. Ann. N.Y. Acad. Sci. 593, 181–187.CrossRefPubMedGoogle Scholar
  50. 50.
    Leach, D.R., Krummel, M.F. and Allison, J.P. (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736.CrossRefPubMedGoogle Scholar
  51. 51.
    Iwai, Y., Terawaki, S. and Honjo, T. (2005) PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int. Immunol. 17, 133–144.CrossRefPubMedGoogle Scholar
  52. 52.
    Ryther, R.C., Flynt, A.S., Phillips, J.A., 3rd and Patton, J.G. (2005) siRNA therapeutics: big potential from small RNAs. Gene Ther. 12, 5–11.CrossRefPubMedGoogle Scholar
  53. 53.
    Carette, J.E., Overmeer, R.M., Schagen, F.H., Alemany, R., Barski, O.A., Gerritsen, W.R. et al. (2004) Conditionally replicating adenoviruses expressing short hairpin RNAs silence the expression of a target gene in cancer cells. Cancer Res. 64, 2663–2667.CrossRefPubMedGoogle Scholar
  54. 54.
    Song, J., Pang, S., Lu, Y., Yokoyama, K.K., Zheng, J.Y. and Chiu, R. (2004) Gene silencing in androgen-responsive prostate cancer cells from the tissue-specific prostate-specific antigen promoter. Cancer Res. 64, 7661–7663.CrossRefPubMedGoogle Scholar
  55. 55.
    Schiffelers, R.M., Ansari, A., Xu, J., Zhou, Q., Tang, Q., Storm, G. et al. (2004) Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res. 32, e149.CrossRefPubMedGoogle Scholar
  56. 56.
    Sumimoto, H., Miyagishi, M., Miyoshi, H., Yamagata, S., Shimizu, A., Taira, K. et al. (2004) Inhibition of growth and invasive ability of melanoma by inactivation of mutated BRAF with lentivirus-mediated RNA interference. Oncogene 23, 6031–6039.CrossRefPubMedGoogle Scholar
  57. 57.
    Sumimoto, H., Yamagata, S., Shimizu, A., Miyoshi, H., Mizuguchi, H., Hayakawa, T. et al. (2005) Gene therapy for human small-cell lung carcinoma by inactivation of Skp-2 with virally mediated RNA interference. Gene Ther. 12, 95–100.CrossRefPubMedGoogle Scholar
  58. 58.
    Duxbury, M.S., Ito, H., Benoit, E., Zinner, M.J., Ashley, S.W. and Whang, E.E. (2004) Retrovirally mediated RNA interference targeting the M2 subunit of ribonucleotide reductase: A novel therapeutic strategy in pancreatic cancer. Surgery 136, 261–269.CrossRefPubMedGoogle Scholar
  59. 59.
    Brummelkamp, T.R., Bernards, R. and Agami, R. (2002) Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2, 243–247.CrossRefPubMedGoogle Scholar
  60. 60.
    Chen, J., Wall, N.R., Kocher, K., Duclos, N., Fabbro, D., Neuberg, D. et al. (2004) Stable expression of small interfering RNA sensitizes TEL-PDGFbetaR to inhibition with imatinib or rapamycin. J. Clin. Invest. 113, 1784–1791.PubMedGoogle Scholar
  61. 61.
    Chen, L.M., Le, H.Y., Qin, R.Y., Kumar, M., Du, Z.Y., Xia, R.J. et al. (2005) Reversal of the phenotype by K-rasval12 silencing mediated by adenovirus-delivered siRNA in human pancreatic cancer cell line Panc-1. World J. Gastroenterol. 11, 831–838.PubMedGoogle Scholar
  62. 62.
    Uchida, H., Tanaka, T., Sasaki, K., Kato, K., Dehari, H., Ito, Y. et al. (2004) Adenovirus-mediated transfer of siRNA against survivin induced apoptosis and attenuated tumor cell growth in vitro and in vivo. Mol. Ther. 10, 162–171.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of PathologyJohns Hopkins School of MedicineBaltimoreUSA
  2. 2.Departments of Pathology, Oncology, Obstetrics, and Gynecology, and Molecular Microbiology and ImmunologyJohns Hopkins School of MedicineBaltimoreUSA

Personalised recommendations