Abstract
The effect of IFN-α on the immunosuppressive tumor microenvironment is not fully understood. We previously reported that intratumoral IFN-α gene transduction decreased the frequency of regulatory T cells (Tregs) in the tumor by inducing the secretion of IL-6 from dendritic cells. In this study, we examined whether IFN-α affects the trafficking of Tregs to the tumor. Since CT26 cells expressed CCL17 among Treg-attracting chemokines, we focused on its role in IFN-α-mediated Treg suppression. IFN-α directly suppressed CCL17 production from CT26 cells in vitro, and IFN-α transduction reduced CCL17 expression in tumors in vivo. Next, to investigate whether CCL17 downregulation is related to the suppression of Treg trafficking, CCL17-downregulated CT26 cells produced using short hairpin RNA (CT26-shCCL17) were inoculated into mice. The frequency of Tregs in CT26-shCCL17 tumors was reduced and tumor growth was suppressed. Finally, to examine the combinatorial effect of IFN-α expression with CCL17 downregulation, IFN-α was transduced into CT26-shCCL17 tumors. This resulted in an elevation of CT26-specific CD8+ T cells and the complete eradication of tumors. This study shows a novel mechanism of IFN-α-mediated Treg suppression, and combining IFN-α gene therapy with strong CCL17 downregulation could offer a promising strategy for the treatment of cancer.
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References
Pfeffer LM, Dinarello CA, Herberman RB, Williams BR, Borden EC, Walter MR, et al. Biological properties of recombinant alpha-interferons: 40th anniversary of the discovery of interferons. Cancer Res. 1998;58:2489–99.
Ferrantini M, Capone I, Belardelli F. Interferon-alpha and cancer: mechanisms of action and new perspectives of clinical use. Biochimie. 2007;89:884–93.
Talpaz M, Hehlmann R, Quintas-Cardama A, Mercer J, Cortes J. Re-emergence of interferon-alpha in the treatment of chronic myeloid leukemia. Leukemia. 2013;27:803–12.
Tarhini AA, Gogas H, Kirkwood JM. IFN-alpha in the treatment of melanoma. J Immunol. 2012;189:3789–93.
Rosenblatt J, McDermott DF. Immunotherapy for renal cell carcinoma. Hematol Oncol Clin North Am. 2011;25:793–812.
Escobar G, Moi D, Ranghetti A, Ozkal-Baydin P, Squadrito ML, Kajaste-Rudnitski A, Bondanza A, et al. Genetic engineering of hematopoiesis for targeted IFN-alpha delivery inhibits breast cancer progression. Sci Transl Med. 2014;6:217ra3.
Hatanaka K, Suzuki K, Miura Y, Yoshida K, Ohnami S, Kitade T, et al. Interferon-alpha and antisense K-ras RNA combination gene therapy against pancreatic cancer. J Gene Med. 2004;6:1139–48.
Ohashi M, Yoshida K, Kushida M, Miura Y, Ohnami S, Ikarashi Y, et al. Adenovirus-mediated interferon alpha gene transfer induces regional direct cytotoxicity and possible systemic immunity against pancreatic cancer. Br J Cancer. 2005;93:441–9.
Narumi K, Kondoh A, Udagawa T, Hara H, Goto N, Ikarashi Y, et al. Administration route-dependent induction of antitumor immunity by interferon-alpha gene transfer. Cancer Sci. 2010;101:1686–94.
Narumi K, Udagawa T, Kondoh A, Kobayashi A, Hara H, Ikarashi Y, et al. In vivo delivery of interferon-alpha gene enhances tumor immunity and suppresses immunotolerance in reconstituted lymphopenic hosts. Gene Ther. 2012;19:34–48.
Hara H, Kobayashi A, Narumi K, Kondoh A, Yoshida K, Nishimoto T, et al. Intratumoral interferon-alpha gene transfer enhances tumor immunity after allogeneic hematopoietic stem cell transplantation. Cancer Immunol Immunother. 2009;58:1007–21.
Hara H, Kobayashi A, Yoshida K, Ohashi M, Ohnami S, Uchida E, et al. Local interferon-alpha gene therapy elicits systemic immunity in a syngeneic pancreatic cancer model in hamster. Cancer Sci. 2007;98:455–63.
Aida K, Miyakawa R, Suzuki K, Narumi K, Udagawa T, Yamamoto Y, et al. Suppression of Tregs by anti-glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon-alpha gene therapy for pancreatic cancer. Cancer Sci. 2014;105:159–67.
Hashimoto H, Ueda R, Narumi K, Heike Y, Yoshida T, Aoki K. Type I IFN gene delivery suppresses regulatory T cells within tumors. Cancer Gene Ther. 2014;21:532–41.
Sather BD, Treuting P, Perdue N, Miazqowicz M, Fontenot JD, Rudensky AY, et al. Altering the distribution of Foxp3( + ) regulatory T cells results in tissue-specific inflammatory disease. J Exp Med. 2007;204:1335–47.
Dudda JC, Perdue N, Bachtanian E, Campbell DJ. Foxp3 + regulatory T cells maintain immune homeostasis in the skin. J Exp Med. 2008;205:1559–65.
Fu H, Kishore M, Gittens B, Wang G, Coe D, Komarowska I, et al. Self-recognition of the endothelium enables regulatory T-cell trafficking and defines the kinetics of immune regulation. Nat Commun. 2014;5:3436.
Anz D, Rapp M, Eiber S, Koelzer VH, Thaler R, Haubner S, et al. Suppression of intratumoral CCL22 by type i interferon inhibits migration of regulatory T cells and blocks cancer progression. Cancer Res. 2015;75:4483–93.
Aoki K, Barker C, Danthinne X, Imperiale MJ, Nabel GJ. Efficient generation of recombinant adenoviral vectors by Cre-lox recombination in vitro. Mol Med. 1999;5:224–31.
Nakano M, Aoki K, Matsumoto N, Ohnami S, Hatanaka K, Hibi T, et al. Suppression of colorectal cancer growth using an adenovirus vector expressing an antisense K-ras RNA. Mol Ther. 2001;3:491–9.
Ishida T, Ueda R. CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci. 2006;97:1139–46.
Mizukami Y, Kono K, Kawaguchi Y, Akaike H, Kamimura K, Sugai H, et al. CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3 + regulatory T cells in gastric cancer. Int J Cancer. 2008;122:2286–93.
Tan MC, Goedegebuure PS, Belt BA, Flaherty B, Sankpal N, Gillanders WE, et al. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol. 2009;182:1746–55.
Porta C, Rimoldi M, Raes G, Brys L, Ghezzi P, Di Liberto D, et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. Proc Natl Acad Sci USA. 2009;106:14978–83.
Katakura T, Miyazaki M, Kobayashi M, Herndon DN, Suzuki F. CCL17 and IL-10 as effectors that enable alternatively activated macrophages to inhibit the generation of classically activated macrophages. J Immunol. 2004;172:1407–13.
Bacher N, Raker V, Hofmann C, Graulich E, Schwenk M, Baumgrass R, et al. Interferon-alpha suppresses cAMP to disarm human regulatory T cells. Cancer Res. 2013;73:5647–56.
Pace L, Vitale S, Dettori B, Palombi C, La Sorsa V, Belardelli F, et al. APC activation by IFN-alpha decreases regulatory T cell and enhances Th cell functions. J Immunol. 2010;184:5969–79.
Wirnsberger G, Hebenstreit D, Posselt G, Horejs-Hoeck J, Duschl A. IL-4 induces expression of TARC/CCL17 via two STAT6 binding sites. Eur J Immunol. 2006;36:1882–91.
Maier E, Wirnsberger G, Horejs-Hoeck J, Duschl A, Hebenstreit D. Identification of a distal tandem STAT6 element within the CCL17 locus. Hum Immunol. 2007;68:986–92.
Fulkerson PC, Zimmermann N, Hassman LM, Finkelman FD, Rothenberg ME. Pulmonary chemokine expression is coordinately regulated by STAT1, STAT6, and IFN-gamma. J Immunol. 2004;173:7565–74.
Gupta S, Jiang M, Pernis AB. IFN-alpha activates Stat6 and leads to the formation of Stat2:Stat6 complexes in B cells. J Immunol. 1999;163:3834–41.
Hervas-Stubbs S, Perez-Gracia JL, Rouzaut A, Sanmamed MF, Le Bon A, Melero I. Direct effects of type I interferons on cells of the immune system. Clin Cancer Res. 2011;17:2619–27.
Komine M, Kakinuma T, Kagami S, Hanakawa Y, Hashimoto K, Tamaki K. Mechanism of thymus- and activation-regulated chemokine (TARC)/CCL17 production and its modulation by roxithromycin. J Invest Dermatol. 2005;125:491–8.
Acknowledgements
This work was supported in part by grants-in-aid for Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (18ck0106358h0002 and 18ak0101043h0104) and grants from the National Cancer Center Research and Development Fund (26-A-11, 26-A-12, 29-A-2, and 29-A-7).
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Hirata, A., Hashimoto, H., Shibasaki, C. et al. Intratumoral IFN-α gene delivery reduces tumor-infiltrating regulatory T cells through the downregulation of tumor CCL17 expression. Cancer Gene Ther 26, 334–343 (2019). https://doi.org/10.1038/s41417-018-0059-5
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DOI: https://doi.org/10.1038/s41417-018-0059-5
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