Intratumoral IL-28B Gene Delivery Elicits Antitumor Effects by Remodeling of the Tumor Microenvironment in H22-Bearing Mice

Overview

Journal J Immunol Res

Publisher Wiley

Specialty Allergy & Immunology

Date 2022 Aug 8

PMID 35935577

Authors

Zhi Li

Jianghua Wang

Chong Chen

Qi He

Xiaoying Xu

Zejiao Da

Bo Wang

Meng Wang

Xiaotong Gao

Guochao Zhang

Qi Gao

Xiaoli Si

Yanping Luo

Xingming Ma

Affiliations

Soon will be listed here.

Abstract

IL-28B, belonging to type III interferons (IFN-s), exhibits a potent antitumor activity with reduced regulated T cells (Tregs) population, yet the effect of IL-28B on the tumor microenvironment (TME) and if IL-28B can downregulate Tregs directly are still unknown. In this study, we investigated the effects of IL-28B on Tregs in the spleen and TME in H22 tumor-bearing mice and verified the downregulation of IL-28B on Tregs . We found that rAd-mIL-28B significantly inhibited tumor growth and reduced the frequency of splenic CD4Foxp3 T cells. The levels of CXCL13, ICAM-1, MCP-5, and IL-7 in the serum, and the levels of IL-15 and sFasL in the tumor tissue decreased significantly after rAd-mIL-28B treatment relative to rAd-EGFP. Furthermore, the percentage of CD8 cells in the TME was significantly increased in the rAd-mIL-28B group compared with the untreated group. , splenocytes were stimulated with anti-CD3/CD28 and IL-2 in the presence of TGF- with or without IL-28B for three days and followed by flow cytometric, RT-PCR, and IL-10 production analysis. The results showed that IL-28B significantly reduced the proportion of induced Foxp3 cells. It demonstrated that IL-28B may be used as a promising immunotherapy strategy against cancer.

References

Wculek S, Cueto F, Mujal A, Melero I, Krummel M, Sancho D . Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2019; 20(1):7-24. DOI: 10.1038/s41577-019-0210-z. View

Kim Y, Kim S, Kim C, Kim I, Cho M, Kim N . Association of serum and intratumoral cytokine profiles with tumor stage and neutrophil lymphocyte ratio in colorectal cancer. Anticancer Res. 2014; 34(7):3481-7. View

Morrow M, Pankhong P, Laddy D, Schoenly K, Yan J, Cisper N . Comparative ability of IL-12 and IL-28B to regulate Treg populations and enhance adaptive cellular immunity. Blood. 2009; 113(23):5868-77. PMC: 2700323. DOI: 10.1182/blood-2008-11-190520. View

Luo Y, Zhang G, Liu X, Yuan M, Gao Q, Gao H . Therapeutic and immunoregulatory effects of water-soluble alkaloids E2-a from Sophora moorcroftiana seeds as a novel potential agent against echinococcosis in experimentally protoscolex-infected mice. Vet Res. 2018; 49(1):100. PMC: 6389144. DOI: 10.1186/s13567-018-0596-9. View

Deng W, Lira V, Hudson T, Lemmens E, Hanson W, Flores R . Recombinant promotes tumor rejection by CD8 T cell-dependent remodeling of the tumor microenvironment. Proc Natl Acad Sci U S A. 2018; 115(32):8179-8184. PMC: 6094133. DOI: 10.1073/pnas.1801910115. View

Tan C, Hu W, He Y, Zhang Y, Zhang G, Xu Y . Cytokine-mediated therapeutic resistance in breast cancer. Cytokine. 2018; 108:151-159. DOI: 10.1016/j.cyto.2018.03.020. View

Donnelly R, Kotenko S . Interferon-lambda: a new addition to an old family. J Interferon Cytokine Res. 2010; 30(8):555-64. PMC: 2925029. DOI: 10.1089/jir.2010.0078. View

Togashi Y, Shitara K, Nishikawa H . Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat Rev Clin Oncol. 2019; 16(6):356-371. DOI: 10.1038/s41571-019-0175-7. View

Sasidharan Nair V, Elkord E . Immune checkpoint inhibitors in cancer therapy: a focus on T-regulatory cells. Immunol Cell Biol. 2018; 96(1):21-33. DOI: 10.1111/imcb.1003. View

10.

Ray A, Nofchissey R, Khan M, Reidy M, Lerner M, Wu X . The role of sex in the innate and adaptive immune environment of metastatic colorectal cancer. Br J Cancer. 2020; 123(4):624-632. PMC: 7435180. DOI: 10.1038/s41416-020-0913-8. View

11.

Liu Z, Wang M, Ren H, Qu W, Sun L, Zhang Q . Interleukin 7 signaling prevents apoptosis by regulating bcl-2 and bax via the p53 pathway in human non-small cell lung cancer cells. Int J Clin Exp Pathol. 2014; 7(3):870-81. PMC: 3971289. View

12.

Nardone V, Botta C, Caraglia M, Martino E, Ambrosio M, Carfagno T . Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse. Cancer Biol Ther. 2016; 17(11):1213-1220. PMC: 5137493. DOI: 10.1080/15384047.2016.1235666. View

13.

Shirley S, Lundberg C, Heller R . Electrotransfer of IL-15/IL-15Rα Complex for the Treatment of Established Melanoma. Cancers (Basel). 2020; 12(10). PMC: 7589551. DOI: 10.3390/cancers12103072. View

14.

Conlon K, Miljkovic M, Waldmann T . Cytokines in the Treatment of Cancer. J Interferon Cytokine Res. 2018; 39(1):6-21. PMC: 6350412. DOI: 10.1089/jir.2018.0019. View

15.

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(12):532-41. DOI: 10.1038/cgt.2014.60. View

16.

Conti I, Rollins B . CCL2 (monocyte chemoattractant protein-1) and cancer. Semin Cancer Biol. 2004; 14(3):149-54. DOI: 10.1016/j.semcancer.2003.10.009. View

17.

Peng S, Lyford-Pike S, Akpeng B, Wu A, Hung C, Hannaman D . Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine. Cancer Immunol Immunother. 2012; 62(1):171-82. PMC: 3543472. DOI: 10.1007/s00262-012-1322-5. View

18.

Tallerico R, Cristiani C, Staaf E, Garofalo C, Sottile R, Capone M . IL-15, TIM-3 and NK cells subsets predict responsiveness to anti-CTLA-4 treatment in melanoma patients. Oncoimmunology. 2017; 6(2):e1261242. PMC: 5353942. DOI: 10.1080/2162402X.2016.1261242. View

19.

Luo Y, Ma X, Liu X, Lu X, Niu H, Yu H . IL-28B down-regulates regulatory T cells but does not improve the protective immunity following tuberculosis subunit vaccine immunization. Int Immunol. 2015; 28(2):77-85. PMC: 4885220. DOI: 10.1093/intimm/dxv061. View

20.

Chen X, Zhu B, Luo Y, Zhang D, Zhang L, Zhu H . Interleukin-28B Plays a Therapeutic Role on Mouse U14 Cervical Cancer Cells by Down-Regulating CD4+CD25+FoxP3+Regulatory T Cells In Vivo. Int J Gynecol Cancer. 2015; 25(8):1369-76. DOI: 10.1097/IGC.0000000000000528. View