固有免疫细胞上Siglec在肿瘤中作用的研究进展与展望

doi:10.19401/j.cnki.1007-3639.2022.12.012

摘要/Abstract

摘要：

免疫治疗给恶性肿瘤患者带来了新的希望。然而，常见的免疫治疗靶点，例如细胞毒性T淋巴细胞相关抗原4（cytotoxic T lymphocyte-associated antigen-4，CTLA-4）、程序性死亡[蛋白]配体-1（programmed death ligand-1，PD-L1）在患者中阳性表达率低，只有少部分患者能从免疫治疗中获益，因此寻找新的免疫治疗靶点对于提高免疫治疗的响应率和效果极其重要。近期的研究提示唾液酸结合免疫球蛋白型凝集素（sialic acid-binding immunoglobulin-type lectin，Siglec）家族在巨噬细胞、自然杀伤（natural killer，NK）细胞和树突状细胞（dendritic cell，DC）等固有免疫细胞上表达丰富，并与肿瘤的发生、发展存在许多联系，有可能成为免疫治疗的下一个新靶点。在巨噬细胞上不同的Siglecs发挥不同的作用，Siglec-1增强巨噬细胞的抗原呈递作用，从而增强CD8⁺T细胞的杀伤作用；Siglec-7和Siglec-9诱导肿瘤相关巨噬细胞（tumor-associated macrophage，TAM）向免疫抑制性TAM分化从而影响免疫微环境；Siglec-10与CD24相互作用保护肿瘤细胞免受巨噬细胞的攻击，Siglec-15也表现出类似PD-L1的相关作用，这些研究提示其有可能是全新的免疫检查点。NK细胞上高表达Siglec-7和Siglec-9，通过消除NK细胞表面的顺式相互作用，这些Siglec展现出免疫抑制作用。肿瘤表面高表达的唾液酸糖蛋白与NK细胞表面的Siglec相结合从而抑制NK细胞的杀伤作用，通过消除肿瘤表面的唾液酸可以增强NK细胞的杀伤力。有方案设想通过构建高亲合顺式配体来增强NK细胞杀伤力，但发现顺式配体的浓度会对NK细胞的杀伤力造成截然不同的影响，提示唾液酸存在某种动态平衡从而影响免疫反应。DC表面的Siglec-3和Siglec-9会与肿瘤黏蛋白相结合，诱导DC凋亡和减少免疫相关分子的产生进而造成免疫逃逸。在小鼠实验中证实相关Siglec影响DC的抗原呈递和免疫相关因子的表达。本综述总结了近期在固有免疫系统中，Siglec与肿瘤之间的相互作用以及Siglec影响肿瘤发生、发展的相关研究进展，讨论该家族成员作为免疫治疗新靶点的可能。

关键词: Siglec, 巨噬细胞, 自然杀伤细胞, 树突状细胞, 免疫检查点

Abstract:

Immunotherapy brings hope to those patients suffering from malignant tumor. However, common immunotherapy targets, such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed death ligand-1 (PD-L1), have low positive expression rate in patients, and only a few patients can benefit from immunotherapy. Therefore, finding new immunotherapy targets is extremely important for improving the response rate and effect of immunotherapy. Recent studies have suggested that sialic acid-binding immunoglobulin-type lectin (Siglec) family members are abundantly expressed in innate immune cells, such as macrophages, natural killer (NK) cells and dendritic cells (DC), and are shown to be related to the development of tumors. Different Siglecs play different roles in macrophages, and Siglec-1 enhances the antigen presentation of macrophages and thus the killing effect of CD8⁺ T cells. Siglec-7 and Siglec-9 induce the differentiation of tumor-associated macrophages (TAM) to immunosuppressive TAM thus affecting the immune microenvironment. Siglec-10 interacts with CD24 to protect tumor cells from macrophage attack, and Siglec-15 also exhibits PD-L1-like related effects, which suggests that it may be a novel immune checkpoint. Siglec-7 and Siglec-9 are highly expressed in NK cells, and these Siglecs exhibit immunosuppressive effects by eliminating cis interactions on the surface of NK cells. The highly expressed sialic acid glycoprotein on the tumor surface would bind to Siglecs on the NK cell surface thereby inhibiting the killing effect of NK cells, and the killing effect of NK cells could be enhanced by eliminating sialic acid on the tumor surface. A proposal to enhance NK cell killing by constructing high-affinity cis-ligands revealed that the concentration of cis-ligands had a very different effect on NK cell killing, suggesting that there is a dynamic balance of sialic acid that affects immune reaction. Siglec-3 and Siglec-9 on the surface of DC bind to tumor mucin, inducing DC apoptosis and reducing the production of immune-related molecules, thereby causing immune escape. The related Siglec has been shown to affect the expression of antigen presentation and immune-related factors in DC in mouse experiments. In this review, we summarized the recent studies of Siglecs in the innate immune system on how they interact with tumors and affecting tumor development, and discussed the potential of them as novel targets for immunotherapy.

Key words: Siglec, Macrophage, Natural killer cell, Dendritic cell, Immune checkpoint

中图分类号:

R730.51

郭朝阳, 胡镜宙. 固有免疫细胞上Siglec在肿瘤中作用的研究进展与展望[J]. 中国癌症杂志, 2022, 32(12): 1235-1241.

GUO Zhaoyang, HU Jingzhou. Research progress and prospect of Siglec in innate immune cells in tumor[J]. China Oncology, 2022, 32(12): 1235-1241.

参考文献 56

[1]	PERETS R, BAR J, RASCO D W, et al. Safety and efficacy of quavonlimab, a novel anti-CTLA-4 antibody (MK-1308), in combination with pembrolizumab in first-line advanced non-small cell lung cancer[J]. Ann Oncol, 2021, 32(3): 395-403. doi: 10.1016/j.annonc.2020.11.020
[2]	WU S Y, XU Y, CHEN L, et al. Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial[J]. Mol Cancer, 2022, 21(1): 84. doi: 10.1186/s12943-022-01536-6
[3]	AKINLEYE A, RASOOL Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics[J]. J Hematol Oncol, 2019, 12(1): 92. doi: 10.1186/s13045-019-0779-5
[4]	SMITH B A H, BERTOZZI C R. The clinical impact of glycobiology: targeting selectins, Siglecs and mammalian glycans[J]. Nat Rev Drug Discov, 2021, 20(3): 217-243. doi: 10.1038/s41573-020-00093-1 pmid: 33462432
[5]	REILY C, STEWART T J, RENFROW M B, et al. Glycosylation in health and disease[J]. Nat Rev Nephrol, 2019, 15(6): 346-366. doi: 10.1038/s41581-019-0129-4 pmid: 30858582
[6]	CHEN J, ZHANG K, ZHI Y R, et al. Tumor-derived exosomal miR-19b-3p facilitates M2 macrophage polarization and exosomal LINC00273 secretion to promote lung adenocarcinoma metastasis via Hippo pathway[J]. Clin Transl Med, 2021, 11(9): e478. doi: 10.1002/ctm2.478 pmid: 34586722
[7]	CHAMSEDDINE A N, ASSI T, MIR O, et al. Modulating tumor-associated macrophages to enhance the efficacy of immune checkpoint inhibitors: a TAM-pting approach[J]. Pharmacol Ther, 2022, 231: 107986.
[8]	CASSETTA L, FRAGKOGIANNI S, SIMS A H, et al. Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets[J]. Cancer Cell, 2019, 35(4): 588-602.e10. doi: S1535-6108(19)30104-7 pmid: 30930117
[9]	BARKAL A A, BREWER R E, MARKOVIC M, et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy[J]. Nature, 2019, 572(7769): 392-396. doi: 10.1038/s41586-019-1456-0
[10]	WANG J, SUN J W, LIU L, et al. Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy[J]. Nat Med, 2019, 25(4): 656-666. doi: 10.1038/s41591-019-0374-x pmid: 30833750
[11]	DALY J, CARLSTEN M, O'DWYER M. Sugar free: novel immunotherapeutic approaches targeting siglecs and sialic acids to enhance natural killer cell cytotoxicity against cancer[J]. Front Immunol, 2019, 10: 1047. doi: 10.3389/fimmu.2019.01047 pmid: 31143186
[12]	BÜLL C, COLLADO-CAMPS E, KERS-REBEL E D, et al. Metabolic sialic acid blockade lowers the activation threshold of moDCs for TLR stimulation[J]. Immunol Cell Biol, 2017, 95(4): 408-415. doi: 10.1038/icb.2016.105 pmid: 27874015
[13]	CROCKER P R, CLARK E A, FILBIN M, et al. Siglecs: a family of sialic-acid binding lectins[J]. Glycobiology, 1998, 8(2): v.
[14]	DUAN S T, PAULSON J C. Siglecs as immune cell checkpoints in disease[J]. Annu Rev Immunol, 2020, 38: 365-395. doi: 10.1146/annurev-immunol-102419-035900 pmid: 31986070
[15]	CROCKER P R, PAULSON J C, VARKI A. Siglecs and their roles in the immune system[J]. Nat Rev Immunol, 2007, 7(4): 255-266. doi: 10.1038/nri2056 pmid: 17380156
[16]	VAN DE WALL S, SANTEGOETS K C M, VAN HOUTUM E J H, et al. Sialoglycans and siglecs can shape the tumor immune microenvironment[J]. Trends Immunol, 2020, 41(4): 274-285. doi: S1471-4906(20)30021-1 pmid: 32139317
[17]	ESTUS S, SHAW B C, DEVANNEY N, et al. Evaluation of CD33 as a genetic risk factor for Alzheimer's disease[J]. Acta Neuropathol, 2019, 138(2): 187-199. doi: 10.1007/s00401-019-02000-4 pmid: 30949760
[18]	LÄUBLI H, VARKI A. Sialic acid-binding immunoglobulin-like lectins (Siglecs) detect self-associated molecular patterns to regulate immune responses[J]. Cell Mol Life Sci, 2020, 77(4): 593-605. doi: 10.1007/s00018-019-03288-x pmid: 31485715
[19]	BHIDE G P, COLLEY K J. Sialylation of N-glycans: mechanism, cellular compartmentalization and function[J]. Histochem Cell Biol, 2017, 147(2): 149-174. doi: 10.1007/s00418-016-1520-x pmid: 27975143
[20]	HUGONNET M, SINGH P, HAAS Q, et al. The distinct roles of sialyltransferases in cancer biology and onco-immunology[J]. Front Immunol, 2021, 12: 799861.
[21]	SCHAUER R, KAMERLING J P. Exploration of the sialic acid world[J]. Advance Carbohydrate Chem Biochem, 2018, 75: 1-213.
[22]	GONZALEZ-GIL A, SCHNAAR R L. Siglec ligands[J]. Cells, 2021, 10(5): 1260. doi: 10.3390/cells10051260
[23]	BÜLL C, STOEL M A, DEN BROK M H, et al. Sialic acids sweeten a tumor's life[J]. Cancer Res, 2014, 74(12): 3199-3204. doi: 10.1158/0008-5472.CAN-14-0728 pmid: 24830719
[24]	BEATSON R, TAJADURA-ORTEGA V, ACHKOVA D, et al. The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin siglec-9[J]. Nat Immunol, 2016, 17(11): 1273-1281. doi: 10.1038/ni.3552 pmid: 27595232
[25]	JANDUS C, BOLIGAN K F, CHIJIOKE O, et al. Interactions between Siglec-7/9 receptors and ligands influence NK cell-dependent tumor immunosurveillance[J]. J Clin Invest, 2014, 124(4): 1810-1820. doi: 10.1172/JCI65899 pmid: 24569453
[26]	OHNISHI K, KOMOHARA Y, SAITO Y, et al. CD169-positive macrophages in regional lymph nodes are associated with a favorable prognosis in patients with colorectal carcinoma[J]. Cancer Sci, 2013, 104(9): 1237-1244. doi: 10.1111/cas.12212
[27]	SAITO Y, OHNISHI K, MIYASHITA A, et al. Prognostic significance of CD169⁺ lymph node sinus macrophages in patients with malignant melanoma[J]. Cancer Immunol Res, 2015, 3(12): 1356-1363. doi: 10.1158/2326-6066.CIR-14-0180
[28]	OHNISHI K, YAMAGUCHI M, ERDENEBAATAR C, et al. Prognostic significance of CD169-positive lymph node sinus macrophages in patients with endometrial carcinoma[J]. Cancer Sci, 2016, 107(6): 846-852. doi: 10.1111/cas.12929
[29]	ASANO T, OHNISHI K, SHIOTA T, et al. CD169-positive sinus macrophages in the lymph nodes determine bladder cancer prognosis[J]. Cancer Sci, 2018, 109(5): 1723-1730. doi: 10.1111/cas.13565
[30]	ASANO K, NABEYAMA A, MIYAKE Y, et al. CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens[J]. Immunity, 2011, 34(1): 85-95. doi: 10.1016/j.immuni.2010.12.011 pmid: 21194983
[31]	SINGH R, CHOI B K. Siglec1-expressing subcapsular sinus macrophages provide soil for melanoma lymph node metastasis[J]. Elife, 2019, 8: e48916.
[32]	LI W, HAN Y N, SUN C M, et al. Novel insights into the roles and therapeutic implications of MUC1 oncoprotein via regulating proteins and non-coding RNAs in cancer[J]. Theranostics, 2022, 12(3): 999-1011. doi: 10.7150/thno.63654 pmid: 35154471
[33]	RODRIGUEZ E, BOELAARS K, BROWN K, et al. Sialic acids in pancreatic cancer cells drive tumour-associated macrophage differentiation via the Siglec receptors Siglec-7 and Siglec-9[J]. Nat Commun, 2021, 12(1): 1270. doi: 10.1038/s41467-021-21550-4 pmid: 33627655
[34]	JING W Q, ZHANG L, QIN F, et al. Targeting macrophages for cancer therapy disrupts bone homeostasis and impairs bone marrow erythropoiesis in mice bearing Lewis lung carcinoma tumors[J]. Cell Immunol, 2018, 331: 168-177. doi: S0008-8749(17)30142-9 pmid: 30103869
[35]	THERUVATH J, MENARD M, SMITH B A H, et al. Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication[J]. Nat Med, 2022, 28(2): 333-344. doi: 10.1038/s41591-021-01625-x pmid: 35027753
[36]	YANG L, FENG Y Y, WANG S S, et al. Siglec-7 is an indicator of natural killer cell function in acute myeloid leukemia[J]. Int Immunopharmacol, 2021, 99: 107965.
[37]	TAO L, WANG S, YANG L, et al. Reduced Siglec-7 expression on NK cells predicts NK cell dysfunction in primary hepatocellular carcinoma[J]. Clin Exp Immunol, 2020, 201(2): 161-170. doi: 10.1111/cei.13444 pmid: 32319079
[38]	BENMERZOUG S, CHEVALIER M F, VILLIER L, et al. Siglec-7 may limit natural killer cell-mediated antitumor responses in bladder cancer patients[J]. Eur Urol Open Sci, 2021, 34: 79-82.
[39]	HERNÁNDEZ-CASELLES T, MIGUEL R C S, RUIZ-ALCARAZ A J, et al. CD33 (siglec-3) inhibitory function: role in the NKG2D/DAP10 activating pathway[J]. J Immunol Res, 2019, 2019: 6032141.
[40]	NICOLL G, AVRIL T, LOCK K, et al. Ganglioside GD3 expression on target cells can modulate NK cell cytotoxicity via siglec-7-dependent and-independent mechanisms[J]. Eur J Immunol, 2003, 33(6): 1642-1648. doi: 10.1002/eji.200323693
[41]	KAWASAKI Y, ITO A, WITHERS D A, et al. Ganglioside DSGb5, preferred ligand for Siglec-7, inhibits NK cell cytotoxicity against renal cell carcinoma cells[J]. Glycobiology, 2010, 20(11): 1373-1379. doi: 10.1093/glycob/cwq116 pmid: 20663960
[42]	DALY J, SARKAR S, NATONI A, et al. Targeting hypersialylation in multiple myeloma represents a novel approach to enhance NK cell-mediated tumor responses[J]. Blood Adv, 2022, 6(11): 3352-3366. doi: 10.1182/bloodadvances.2021006805
[43]	WISNOVSKY S, MÖCKL L, MALAKER S A, et al. Genome-wide CRISPR screens reveal a specific ligand for the glycan-binding immune checkpoint receptor Siglec-7[J]. Proc Natl Acad Sci USA, 2021, 118(5): e2015024118.
[44]	FONG J J, TSAI C M, SAHA S, et al. Siglec-7 engagement by GBS β-protein suppresses pyroptotic cell death of natural killer cells[J]. Proc Natl Acad Sci USA, 2018, 115(41): 10410-10415. doi: 10.1073/pnas.1804108115 pmid: 30254166
[45]	HUANG C H, LIAO Y J, FAN T H, et al. A developed NK-92MI cell line with siglec-7neg phenotype exhibits high and sustainable cytotoxicity against leukemia cells[J]. Int J Mol Sci, 2018, 19(4): E1073.
[46]	HONG S, YU C, RODRIGUES E, et al. Modulation of siglec-7 signaling via in situ-created high-affinity cis-ligands[J]. ACS Cent Sci, 2021, 7(8): 1338-1346. doi: 10.1021/acscentsci.1c00064
[47]	GRABENSTEIN S, BARNARD K N, ANIM M, et al. Deacetylated sialic acids modulates immune mediated cytotoxicity via the sialic acid-Siglec pathway[J]. Glycobiology, 2021, 31(10): 1279-1294. doi: 10.1093/glycob/cwab068 pmid: 34192335
[48]	IBARLUCEA-BENITEZ I, WEITZENFELD P, SMITH P, et al. Siglecs-7/9 function as inhibitory immune checkpoints in vivo and can be targeted to enhance therapeutic antitumor immunity[J]. Proc Natl Acad Sci USA, 2021, 118(26): e2107424118.
[49]	DE LA ROCHERE P, GUIL-LUNA S, DECAUDIN D, et al. Humanized mice for the study of immuno-oncology[J]. Trends Immunol, 2018, 39(9): 748-763. doi: S1471-4906(18)30125-X pmid: 30077656
[50]	WANG J Y, MANNI M, BÄRENWALDT A, et al. Siglec receptors modulate dendritic cell activation and antigen presentation to T cells in cancer[J]. Front Cell Dev Biol, 2022, 10: 828916.
[51]	LÜBBERS J, RODRÍGUEZ E, VAN KOOYK Y. Modulation of immune tolerance via siglec-sialic acid interactions[J]. Front Immunol, 2018, 9: 2807. doi: 10.3389/fimmu.2018.02807 pmid: 30581432
[52]	ISHIDA A, OHTA M, TODA M, et al. Mucin-induced apoptosis of monocyte-derived dendritic cells during maturation[J]. Proteomics, 2008, 8(16): 3342-3349. doi: 10.1002/pmic.200800039 pmid: 18690650
[53]	OHTA M, ISHIDA A, TODA M, et al. Immunomodulation of monocyte-derived dendritic cells through ligation of tumor-produced mucins to siglec-9[J]. Biochem Biophys Res Commun, 2010, 402(4): 663-669. doi: 10.1016/j.bbrc.2010.10.079
[54]	DING Y Y, GUO Z H, LIU Y Q, et al. The lectin Siglec-G inhibits dendritic cell cross-presentation by impairing MHC class Ⅰ-peptide complex formation[J]. Nat Immunol, 2016, 17(10): 1167-1175. doi: 10.1038/ni.3535
[55]	AFFANDI A J, GRABOWSKA J, OLESEK K, et al. Selective tumor antigen vaccine delivery to human CD169⁺ antigen-presenting cells using ganglioside-liposomes[J]. PNAS, 2020, 117(44): 27528-27539. doi: 10.1073/pnas.2006186117
[56]	LAMPRINAKI D, GARCIA-VELLO P, MARCHETTI R, et al. Siglec-7 mediates immunomodulation by colorectal cancer-associated Fusobacterium nucleatum ssp. animalis[J]. Front Immunol, 2021, 12: 744184.