甲状腺癌免疫微环境及免疫治疗的研究进展

doi:10.16139/j.1007-9610.2025.02.12

摘要/Abstract

摘要：

甲状腺癌是最常见的内分泌恶性肿瘤。虽然大多数病人通过手术和传统治疗获得良好预后，但15%~20%的甲状腺乳头状癌以及未分化癌和髓样癌病人仍缺乏有效治疗方案。肿瘤免疫微环境在甲状腺癌的发生、发展及耐药性中发挥着重要作用。本文综述了甲状腺癌免疫微环境中的关键免疫细胞，包括肿瘤相关巨噬细胞、骨髓来源抑制性细胞、肥大细胞、自然杀伤细胞和T淋巴细胞，并探讨这些细胞在肿瘤免疫逃逸过程中的功能与作用机制。免疫治疗已成为晚期甲状腺癌治疗的新方向，本文总结了目前在免疫检查点抑制剂、靶向巨噬细胞治疗和肿瘤疫苗进行的尝试与取得的进展。

关键词: 甲状腺癌, 免疫微环境, 免疫治疗

Abstract:

Thyroid cancer is the most common endocrine malignancy. Although most patients achieve good prognosis through surgery and conventional treatments, approximately 15%-20% of patients with papillary thyroid cancer and the anaplastic and medullary thyroid cancers still lack effective treatment options. The tumor immune microenvironment plays a critical role in the occurrence, progression, and drug resistance of thyroid cancer. This review focused on the key immune cells in thyroid cancer, including tumor-associated macrophages, myeloid-derived suppressor cells, mast cells, natural killer cells, and T lymphocytes, and explored their roles and mechanisms in tumor immune evasion. Immunotherapy has become an emerging treatment strategy for advanced thyroid cancer, we summarized the attempts and advances in immune checkpoint inhibitors, targeted macrophage therapy and tumor vaccines.

Key words: Thyroid cancer, Immune microenvironment, Immunotherapy

中图分类号:

R736.1

廖振宇, 朱文鑫综述, 严佶祺审校. 甲状腺癌免疫微环境及免疫治疗的研究进展[J]. 外科理论与实践, 2025, 30(2): 165-170.

LIAO Zhenyu, ZHU Wenxin, YAN Jiqi. Research progress on the immune microenvironment and immunotherapy of thyroid cancer[J]. Journal of Surgery Concepts & Practice, 2025, 30(2): 165-170.

图/表 1

参考文献 51

[1]	LA VECCHIA C, MALVEZZI M, BOSETTI C, et al. Thyroid cancer mortality and incidence: a global overview[J]. Int J Cancer, 2015, 136(9):2187-2195. doi: 10.1002/ijc.29251 pmid: 25284703
[2]	CHEN A Y, JEMAL A, WARD E M. Increasing incidence of differentiated thyroid cancer in the United States, 1988-2005[J]. Cancer, 2009, 115(16):3801-3807. doi: 10.1002/cncr.24416 pmid: 19598221
[3]	MAZZAFERRI E L, JHIANG S M. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer[J]. Am J Med, 1994, 97(5):418-428. doi: 10.1016/0002-9343(94)90321-2 pmid: 7977430
[4]	LOPEZ GAVILANEZ E, NAVARRO GRIJALVA M. Studying the incidence of thyroid cancer in Ecuador:2016-2021[J]. Heliyon, 2024, 10(10):e30711.
[5]	SIEGEL R L, MILLER K D, FUCHS H E, et al. Cancer statistics, 2021[J]. CA Cancer J Clin, 2021, 71(1):7-33.
[6]	SUN J, SHI R, ZHANG X, et al. Characterization of immune landscape in papillary thyroid cancer reveals distinct tumor immunogenicity and implications for immunotherapy[J]. Oncoimmunology, 2021, 10(1):e1964189.
[7]	THORSSON V, GIBBS D L, BROWN S D, et al. The immune landscape of cancer[J]. Immunity, 2019, 51(2):411-412. doi: S1074-7613(19)30330-9 pmid: 31433971
[8]	WANG T, SHI J, LI L, et al. Single-cell transcriptome analysis reveals inter-tumor heterogeneity in bilateral papillary thyroid carcinoma[J]. Front Immunol,2022, 13:840811
[9]	WATANABE S, ALEXANDER M, MISHARIN A V, et al. The role of macrophages in the resolution of inflammation[J]. J Clin Invest, 2019, 129(7):2619-2628. doi: 10.1172/JCI124615 pmid: 31107246
[10]	CHRISTOFIDES A, STRAUSS L, YEO A, et al. The complex role of tumor-infiltrating macrophages[J]. Nat Immunol, 2022, 23(8):1148-1156. doi: 10.1038/s41590-022-01267-2 pmid: 35879449
[11]	JUNG K Y, CHO S W, KIM Y A, et al. Cancers with higher density of tumor-associated macrophages were associated with poor survival rates[J]. J Pathol Transl Med, 2015, 49(4):318-324. doi: 10.4132/jptm.2015.06.01 pmid: 26081823
[12]	QING W, FANG W Y, YE L, et al. Density of tumor-associated macrophages correlates with lymph node metastasis in papillary thyroid carcinoma[J]. Thyroid, 2012, 22(9):905-910. doi: 10.1089/thy.2011.0452 pmid: 22870901
[13]	FANG W, YE L, SHEN L, et al. Tumor-associated macrophages promote the metastatic potential of thyroid papillary cancer by releasing CXCL8[J]. Carcinogenesis, 2014, 35(8):1780-1787. doi: 10.1093/carcin/bgu060 pmid: 24608042
[14]	CUNHA L L, MORARI E C, GUIHEN A C, et al. Infiltration of a mixture of immune cells may be related to good prognosis in patients with differentiated thyroid carcinoma[J]. Clin Endocrinol (Oxf), 2012, 77(6):918-925.
[15]	DONADON M, TORZILLI G, CORTESE N, et al. Macrophage morphology correlates with single-cell diversity and prognosis in colorectal liver metastasis[J]. J Exp Med, 2020, 217(11):e20191847.
[16]	MARTINEZ F O, SICA A, MANTOVANI A, et al. Macrophage activation and polarization[J]. Front Biosci, 2008,13:453-461.
[17]	RYDER M, GHOSSEIN R A, RICARTE-FILHO J C, et al. Increased density of tumor-associated macrophages is associated with decreased survival in advanced thyroid cancer[J]. Endocr Relat Cancer, 2008, 15(4):1069-1074.
[18]	SOLITO S, MARIGO I, PINTON L, et al. Myeloid-derived suppressor cell heterogeneity in human cancers[J]. Ann N Y Acad Sci, 2014,1319:47-65.
[19]	XU L, ZHOU C, LIANG Y, et al. Epigenetic modifications in the accumulation and function of myeloid-derived suppressor cells[J]. Front Immunol,2022, 13:1016870
[20]	SUZUKI S, SHIBATA M, GONDA K, et al. Immunosuppression involving increased myeloid-derived suppressor cell levels, systemic inflammation and hypoalbuminemia are present in patients with anaplastic thyroid cancer[J]. Mol Clin Oncol, 2013, 1(6):959-964. doi: 10.3892/mco.2013.170 pmid: 24649277
[21]	APONTE-LÓPEZ A, MUÑOZ-CRUZ S. Mast cells in the tumor microenvironment[J]. Adv Exp Med Biol, 2020,1273:159-173.
[22]	WROBLEWSKI M, BAUER R, CUBAS Córdova M, et al. Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B[J]. Nat Commun, 2017, 8(1):269. doi: 10.1038/s41467-017-00327-8 pmid: 28814715
[23]	MELILLO R M, GUARINO V, AVILLA E, et al. Mast cells have a protumorigenic role in human thyroid cancer[J]. Oncogene, 2010, 29(47):6203-6215. doi: 10.1038/onc.2010.348 pmid: 20729915
[24]	VISCIANO C, LIOTTI F, PREVETE N, et al. Mast cells induce epithelial-to-mesenchymal transition and stem cell features in human thyroid cancer cells through an IL-8-Akt-Slug pathway[J]. Oncogene, 2015, 34(40):5175-5186. doi: 10.1038/onc.2014.441 pmid: 25619830
[25]	SMYTH M J, CRETNEY E, KELLY J M, et al. Activation of NK cell cytotoxicity[J]. Mol Immunol, 2005, 42(4):501-510. doi: 10.1016/j.molimm.2004.07.034 pmid: 15607806
[26]	VYAS M, REQUESENS M, NGUYEN T H, et al. Natural killer cells suppress cancer metastasis by eliminating circulating cancer cells[J]. Front Immunol,2023, 13:1098445
[27]	GOGALI F, PATERAKIS G, RASSIDAKIS G Z, et al. Phenotypical analysis of lymphocytes with suppressive and regulatory properties (Tregs) and NK cells in the pa-pillary carcinoma of thyroid[J]. J Clin Endocrinol Metab, 2012, 97(5):1474-1482.
[28]	YIN M, DI G, BIAN M. Dysfunction of natural killer cells mediated by PD-1 and Tim-3 pathway in anaplastic thyroid cancer[J]. Int Immunopharmacol, 2018,64:333-339.
[29]	WENNERBERG E, PFEFFERLE A, EKBLAD L, et al. Human anaplastic thyroid carcinoma cells are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract NK cells[J]. Clin Cancer Res, 2014, 20(22):5733-5744.
[30]	XIA A, ZHANG Y, XU J, et al. T cell dysfunction in cancer immunity and immunotherapy[J]. Front Immunol,2019, 10:1719 doi: 10.3389/fimmu.2019.01719 pmid: 31379886
[31]	SCHREIBER R D, OLD L J, SMYTH M J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion[J]. Science, 2011, 331(6024):1565-1570. doi: 10.1126/science.1203486 pmid: 21436444
[32]	THOMMEN D S, SCHUMACHER T N. T cell dysfunction in cancer[J]. Cancer Cell, 2018, 33(4):547-562. doi: S1535-6108(18)30116-8 pmid: 29634943
[33]	BASTMAN J J, SERRACINO H S, ZHU Y, et al. Tumor-infiltrating T cells and the PD-1 checkpoint pathway in advanced differentiated and anaplastic thyroid cancer[J]. J Clin Endocrinol Metab, 2016, 101(7):2863-2873. doi: 10.1210/jc.2015-4227 pmid: 27045886
[34]	GLICK A B, WODZINSKI A, FU P, et al. Impairment of regulatory T-cell function in autoimmune thyroid disease[J]. Thyroid, 2013, 23(7):871-878. doi: 10.1089/thy.2012.0514 pmid: 23379353
[35]	HALVORSEN E C, MAHMOUD S M, BENNEWITH K L. Emerging roles of regulatory T cells in tumour progression and metastasis[J]. Cancer Metastasis Rev, 2014, 33(4):1025-1041.
[36]	ARENA A, STIGLIANO A, BELCASTRO E, et al. p53 activation effect in the balance of T regulatory and effector cell subsets in patients with thyroid cancer and autoimmunity[J]. Front Immunol,2021, 12:728381
[37]	FRENCH J D, WEBER Z J, FRETWELL D L, et al. Tumor-associated lymphocytes and increased FoxP3+ regulatory T cell frequency correlate with more aggressive papillary thyroid cancer[J]. J Clin Endocrinol Metab, 2010, 95(5):2325-2333. doi: 10.1210/jc.2009-2564 pmid: 20207826
[38]	IMAM S, PAPARODIS R, SHARMA D, et al. Lymphocytic profiling in thyroid cancer provides clues for failure of tumor immunity[J]. Endocr Relat Cancer, 2014, 21(3):505-516.
[39]	MENICALI E, GUZZETTI M, MORELLI S, et al. Immune landscape of thyroid cancers: new insights[J]. Front Endocrinol (Lausanne),2021, 11:637826
[40]	FRENCH J D, KOTNIS G R, SAID S, et al. Programmed death-1+ T cells and regulatory T cells are enriched in tumor-involved lymph nodes and associated with aggressive features in papillary thyroid cancer[J]. J Clin Endocrinol Metab, 2012, 97(6):E934-E943.
[41]	MEHNERT J M, VARGA A, BROSE M S, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced, PD-L1-positive papillary or follicular thyroid cancer[J]. BMC Cancer, 2019, 19(1):196. doi: 10.1186/s12885-019-5380-3 pmid: 30832606
[42]	DIERKS C, SEUFERT J, AUMANN K, et al. Combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma[J]. Thyroid, 2021, 31(7):1076-1085. doi: 10.1089/thy.2020.0322 pmid: 33509020
[43]	NIU Y, DING Z, DENG X, et al. A novel multimodal therapy for anaplastic thyroid carcinoma: ¹²⁵I seed implantation plus apatinib after surgery[J]. Front Endocrinol (Lausanne),2020, 11:207
[44]	KIM S, CHO S W, MIN H S, et al. The expression of tumor-associated macrophages in papillary thyroid carcinoma[J]. Endocrinol Metab (Seoul), 2013, 28(3):192-198.
[45]	NAOUM G E, MORKOS M, KIM B, et al. Novel targeted therapies and immunotherapy for advanced thyroid cancers[J]. Mol Cancer, 2018, 17(1):51. doi: 10.1186/s12943-018-0786-0 pmid: 29455653
[46]	RATH G M, SCHNEIDER C, DEDIEU S, et al. The C-terminal CD47/IAP-binding domain of thrombospondin-1 prevents camptothecin- and doxorubicin-induced apoptosis in human thyroid carcinoma cells[J]. Biochim Biophys Acta, 2006, 1763(10):1125-1134. pmid: 16962673
[47]	GUO C, MANJILI M H, SUBJECK J R, et al. Therapeutic cancer vaccines: past, present, and future[J]. Adv Cancer Res, 2013,119:421-475.
[48]	LENNERZ V, GROSS S, GALLERANI E, et al. Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors[J]. Cancer Immunol Immunother, 2014, 63(4):381-394. doi: 10.1007/s00262-013-1516-5 pmid: 24487961
[49]	WANG Y, ZHANG J, WU Y, et al. Mannan-modified ade-novirus targeting TERT and VEGFR-2: a universal tumour vaccine[J]. Sci Rep,2015, 5:11275
[50]	SCHOTT M, SEISSLER J, LETTMANN M, et al. Immunotherapy for medullary thyroid carcinoma by dendritic cell vaccination[J]. J Clin Endocrinol Metab, 2001, 86(10):4965-4969.
[51]	SHONKA D C JR., HO A, CHINTAKUNTLAWAR A V, et al. American head and neck society endocrine surgery section and international thyroid oncology group consensus statement on mutational testing in thyroid cancer: defining advanced thyroid cancer and its targeted treatment[J]. Head Neck, 2022, 44(6):1277-1300.