CD1d highly expressed on DCs reduces lung tumor burden by enhancing antitumor immunity

Li,Yifan; Zhao,Chujun; Liu,Jiajing; Lu,Zhou; Lu,Mingfang; Gu,Jie; Liu,Ronghua

doi:10.3892/or.2019.7037

CD1d highly expressed on DCs reduces lung tumor burden by enhancing antitumor immunity

Authors:
- Yifan Li
- Chujun Zhao
- Jiajing Liu
- Zhou Lu
- Mingfang Lu
- Jie Gu
- Ronghua Liu
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Affiliations: Department of Immunology, School of Basic Medical Sciences, and Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China, Northfield Mount Hermon School, Northfield, MA 01354, USA, Department of Thoracic Surgery, The Affiliated Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
Published online on: February 28, 2019 https://doi.org/10.3892/or.2019.7037
Pages: 2679-2688
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Dendritic cells (DCs), as professional antigen‑presenting cells are essential for the initial activation of adaptive antitumor immunity. CD1d is considered to present phospholipid and glycosphingolipid antigens to NKT cells. However, it is currently unknown whether CD1d expression on DCs is capable of enhancing antitumor immunity, particularly T‑cell related immunity. We observed that CD1d was predominantly expressed on DCs in 3LL tumor‑bearing mice, whilst a deficiency of CD1d promoted tumor growth. Notably, CD1d expression on DCs was not only required for presenting antigen to NKT cells, but also markedly promoted CD4+T and CD8+T cell activation, particularly cytotoxic T cells. All the T cells (NKT, CD4+T and CD8+T cells) upregulated CD69, CD107a and IFN‑γ after the adoptive transfer of CD1d‑positive DCs (CD1d+DCs) and tumor growth was suppressed. With regard to the mechanism, we revealed that CD1d+DCs were concomitant with a higher expression of costimulatory molecules (CD40, CD80 and CD86) and MHCI/II, which are essential for DCs to present antigens to T cells. Consistently, CD1d+DCs displayed stronger activation‑associated‑ERK1/2 and NF‑κB signals; whereas JAK2‑STAT3/6 signaling was required for maintaining a high level of CD1d on DCs. In lung cancer patients, the antitumor activities of all the T cells were enhanced with the increase of CD1d+DCs. Analysis of TCGA data revealed that high levels of CD1d indicated better outcomes for patients. Collectively, CD1d enhanced DC‑based antitumor immunity, not only by targeting NKT, but also by activating CD4+T and CD8+T cells. CD1d+DCs may be superior to the bulk population of DCs in cancer immunotherapy.

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1	Escors D: Tumour immunogenicity, antigen presentation and immunological barriers in cancer immunotherapy. New J Sci. 2014(pii): 7345152014.PubMed/NCBI
2	Bandola-Simon J and Roche PA: Dysfunction of antigen processing and presentation by dendritic cells in cancer. Mol Immunol. Apr 5–2018.(Epub ahead of print). pii: S0161-5890(18)30104-4, doi: 10.1016/j.molimm.2018.03.025. View Article : Google Scholar : PubMed/NCBI
3	Cordes LM, Gulley JL and Madan RA: Perspectives on the clinical development of immunotherapy in prostate cancer. Asian J Androl. 20:253–259. 2018. View Article : Google Scholar : PubMed/NCBI
4	Chen YL, Chang MC, Chiang YC, Lin HW, Sun NY, Chen CA, Sun WZ and Cheng WF: Immuno-modulators enhance antigen- specific immunity and anti-tumor effects of mesothelin-specific chimeric DNA vaccine through promoting DC maturation. Cancer Lett. 425:152–163. 2018. View Article : Google Scholar : PubMed/NCBI
5	de Charette M, Marabelle A and Houot R: Turning tumour cells into antigen presenting cells: The next step to improve cancer immunotherapy? Eur J Cancer. 68:134–147. 2016. View Article : Google Scholar : PubMed/NCBI
6	Jung NC, Lee JH, Chung KH, Kwak YS and Lim DS: Dendritic cell-based immunotherapy for solid tumors. Transl Oncol. 11:686–690. 2018. View Article : Google Scholar : PubMed/NCBI
7	Canchis PW, Bhan AK, Landau SB, Yang L, Balk SP and Blumberg RS: Tissue distribution of the non-polymorphic major histocompatibility complex class I-like molecule, CD1d. Immunology. 80:561–565. 1993.PubMed/NCBI
8	Barral DC and Brenner MB: CD1 antigen presentation: How it works. Nat Rev Immunol. 7:929–941. 2007. View Article : Google Scholar : PubMed/NCBI
9	Moody DB and Porcelli SA: Intracellular pathways of CD1 antigen presentation. Nat Rev Immunol. 3:11–22. 2003. View Article : Google Scholar : PubMed/NCBI
10	McEwen-Smith RM, Salio M and Cerundolo V: CD1d-dependent endogenous and exogenous lipid antigen presentation. Curr Opin Immunol. 34:116–125. 2015. View Article : Google Scholar : PubMed/NCBI
11	Brutkiewicz RR, Yunes-Medina L and Liu J: Immune evasion of the CD1d/NKT cell axis. Curr Opin Immunol. 52:87–92. 2018. View Article : Google Scholar : PubMed/NCBI
12	Teo WY, Elghetany MT, Shen J, Man TK, Li X, Chintagumpala M, Su JM, Dauser R, Whitehead W, Adesina AM, et al: Therapeutic implications of CD1d expression and tumor-infiltrating macrophages in pediatric medulloblastomas. J Neurooncol. 120:293–301. 2014. View Article : Google Scholar : PubMed/NCBI
13	Huang E, Liu R, Lu Z, Liu J, Liu X, Zhang D and Chu Y: NKT cells mediate the recruitment of neutrophils by stimulating epithelial chemokine secretion during colitis. Biochem Biophys Res Commun. 474:252–258. 2016. View Article : Google Scholar : PubMed/NCBI
14	Webb TJ, Carey GB, East JE, Sun W, Bollino DR, Kimball AS and Brutkiewicz RR: Alterations in cellular metabolism modulate CD1d-mediated NKT-cell responses. Pathog Dis. 74:742016. View Article : Google Scholar
15	Chung BK, Priatel JJ and Tan R: CD1d Expression and invariant NKT cell responses in herpesvirus infections. Front Immunol. 6:3122015. View Article : Google Scholar : PubMed/NCBI
16	Exley M, Garcia J, Wilson SB, Spada F, Gerdes D, Tahir SM, Patton KT, Blumberg RS, Porcelli S, Chott A, et al: CD1d structure and regulation on human thymocytes, peripheral blood T cells, B cells and monocytes. Immunology. 100:37–47. 2000. View Article : Google Scholar : PubMed/NCBI
17	Brigl M and Brenner MB: CD1: Antigen presentation and T cell function. Annu Rev Immunol. 22:817–890. 2004. View Article : Google Scholar : PubMed/NCBI
18	Männ L, Kochupurakkal N, Martin C, Verjans E, Klingberg A, Sody S, Kraus A, Dalimot J, Bergmüller E, Jung S, et al: CD11c.DTR mice develop a fatal fulminant myocarditis after local or systemic treatment with diphtheria toxin. Eur J Immunol. 46:2028–2042. 2016. View Article : Google Scholar : PubMed/NCBI
19	Wang SS, Liu W, Ly D, Xu H, Qu L and Zhang L: Tumor-infiltrating B cells: Their role and application in anti-tumor immunity in lung cancer. Cell Mol Immunol. 2018.
20	Zhou J, Lai W, Yang W, Pan J, Shen H, Cai Y, Yang C, Ma N, Zhang Y, Zhang R, et al: BLT1 in dendritic cells promotes Th1/Th17 differentiation and its deficiency ameliorates TNBS-induced colitis. Cell Mol Immunol. 15:1047–1056. 2018. View Article : Google Scholar : PubMed/NCBI
21	Zheng Y, Xiong S, Jiang P, Liu R, Liu X, Qian J, Zheng X and Chu Y: Glucocorticoids inhibit lipopolysaccharide-mediated inflammatory response by downregulating microRNA-155: A novel anti-inflammation mechanism. Free Radic Biol Med. 52:1307–1317. 2012. View Article : Google Scholar : PubMed/NCBI
22	Perwitasari O, Cho H, Diamond MS and Gale M Jr: Inhibitor of κB kinase epsilon (IKK(epsilon)), STAT1, and IFIT2 proteins define novel innate immune effector pathway against West Nile virus infection. J Biol Chem. 286:44412–44423. 2011. View Article : Google Scholar : PubMed/NCBI
23	Gentilini MV, Pérez ME, Fernández PM, Fainboim L and Arana E: The tumor antigen N-glycolyl-GM3 is a human CD1d ligand capable of mediating B cell and natural killer T cell interaction. Cancer Immunol Immunother. 65:551–562. 2016. View Article : Google Scholar : PubMed/NCBI
24	Ferguson K, Yadav A, Morey S, Abdullah J, Hrysenko G, Eng JY, Sajjad M, Koury S and Rittenhouse-Olson K: Preclinical studies with JAA-F11 anti-Thomsen-Friedenreich monoclonal antibody for human breast cancer. Future Oncol. 10:385–399. 2014. View Article : Google Scholar : PubMed/NCBI
25	Reis e Sousa C: Dendritic cells in a mature age. Nat Rev Immunol. 6:476–483. 2006. View Article : Google Scholar : PubMed/NCBI
26	Veglia F and Gabrilovich DI: Dendritic cells in cancer: The role revisited. Curr Opin Immunol. 45:43–51. 2017. View Article : Google Scholar : PubMed/NCBI
27	Liu Q, Zhang C, Sun A, Zheng Y, Wang L and Cao X: Tumor- educated CD11b^highIa^low regulatory dendritic cells suppress T cell response through arginase I. J Immunol. 182:6207–6216. 2009. View Article : Google Scholar : PubMed/NCBI
28	Chong TW, Goh FY, Sim MY, Huang HH, Thike AA, Lim WK, Teh BT and Tan PH: CD1d expression in renal cell carcinoma is associated with higher relapse rates, poorer cancer-specific and overall survival. J Clin Pathol. 68:200–205. 2015. View Article : Google Scholar : PubMed/NCBI
29	Sáez de Guinoa J, Jimeno R, Gaya M, Kipling D, Garzón MJ, Dunn-Walters D, Ubeda C and Barral P: CD1d-mediated lipid presentation by CD11c⁺ cells regulates intestinal homeostasis. EMBO J. 37:372018. View Article : Google Scholar
30	Hix LM, Shi YH, Brutkiewicz RR, Stein PL, Wang CR and Zhang M: CD1d-expressing breast cancer cells modulate NKT cell-mediated antitumor immunity in a murine model of breast cancer metastasis. PLoS One. 6:e207022011. View Article : Google Scholar : PubMed/NCBI
31	Liu D, Song L, Brawley VS, Robison N, Wei J, Gao X, Tian G, Margol A, Ahmed N, Asgharzadeh S, et al: Medulloblastoma expresses CD1d and can be targeted for immunotherapy with NKT cells. Clin Immunol. 149:55–64. 2013. View Article : Google Scholar : PubMed/NCBI
32	Oleinika K, Rosser EC, Matei DE, Nistala K, Bosma A, Drozdov I and Mauri C: CD1d-dependent immune suppression mediated by regulatory B cells through modulations of iNKT cells. Nat Commun. 9:6842018. View Article : Google Scholar : PubMed/NCBI
33	Liechtenstein T, Dufait I, Lanna A, Breckpot K and Escors D: Modulating co-stimulation during antigen presentation to enhance cancer immunotherapy. Immunol Endocr Metab Agents Med Chem. 12:224–235. 2012. View Article : Google Scholar : PubMed/NCBI
34	Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M and Escors D: PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8⁺ T cells. EMBO Mol Med. 3:581–592. 2011. View Article : Google Scholar : PubMed/NCBI
35	Liechtenstein T, Dufait I, Bricogne C, Lanna A, Pen J, Breckpot K and Escors D: PD-L1/PD-1 co-stimulation, a brake for T cell activation and a T cell differentiation signal. J Clin Cell Immunol S12:. (pii): 0062012.
36	Merad M, Sathe P, Helft J, Miller J and Mortha A: The dendritic cell lineage: Ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 31:563–604. 2013. View Article : Google Scholar : PubMed/NCBI