程序性死亡受体1/程序性死亡-配体1抑制剂在结核病研究中的进展

doi:10.19983/j.issn.2096-8493.2024141

摘要/Abstract

摘要：

结核病仍然是全球范围内最具威胁的传染性疾病之一。在结核分枝杆菌潜伏感染中,病原体可以长时间处于休眠状态,等待宿主免疫功能下降时再激活。结核病的免疫应答依赖于适应性免疫,特别是T淋巴细胞。其中CD4⁺ T淋巴细胞通过释放γ-干扰素来激活巨噬细胞,而CD8⁺T淋巴细胞则直接杀伤受感染的宿主细胞。长期慢性的感染往往导致T淋巴细胞功能的衰竭,免疫系统无法有效清除病原体。程序性死亡受体1(programmed death 1, PD-1)和程序性死亡配体1(programmed cell death-ligand 1, PD-L1)抑制剂作为免疫检查点抑制剂,已经展现出恢复免疫应答、杀伤肿瘤细胞的强大潜力,并在癌症治疗中得到了广泛应用。然而,在结核病中的作用机制、治疗前景仍需进一步研究。为了更好地推动PD-1和PD-L1抑制剂在传染病领域的应用,作者综述了结核病中T淋巴细胞适应性免疫的特征,PD-1/PD-L1信号通路的功能及在结核病中的作用,并对阻断PD-1/PD-L1通路在结核病治疗中的最新研究进展进行了总结和讨论。旨在为免疫检查点抑制剂在感染性疾病中的应用提供参考。

关键词: 免疫抑制剂, 结核, T淋巴细胞, 综述文献(主题)

Abstract:

Tuberculosis remains one of the most threatening infectious diseases worldwide. In latent Mycobacterium tuberculosis infection, it can remain dormant for long period of time, waiting to be reactivated when the host’s immune function declines. The immune response to Mycobacterium tuberculosis relies on adaptive immunity, particularly T lymphocytes. Among them, CD4⁺ T lymphocytes activate macrophages by releasing interferon-γ, while CD8⁺ T lymphocytes directly kill infected host cells. Long-term chronic infection often leads to T-lymphocyte exhaustion and the immune system is unable to effectively clear pathogens. Programmed death 1(PD-1) and programmed cell death-ligand 1(PD-L1) inhibitors, as immune checkpoint inhibitors, have demonstrated a strong potential for restoring immune response and killing tumor cells, and have been widely used in cancer therapy. However, its functional mechanisms and therapeutic prospect in tuberculosis still need further research. In order to better promote the application of PD-1 and PD-L1 inhibitors in the field of infectious diseases, we reviewed characteristics of T-lymphocyte adaptive immunity in tuberculosis, functions of the PD-1/PD-L1 signaling pathway and their roles in tuberculosis, and summarized and discussed the latest research advances in blocking the PD-1/PD-L1 pathway in tuberculosis treatment, aiming to provide a reference for the application of immune checkpoint inhibitors in infectious diseases.

Key words: Immunosuppressive agents, Tuberculosis, T-lymphocytes, Review literature as topic

中图分类号:

杨舒琪, 李锋. 程序性死亡受体1/程序性死亡-配体1抑制剂在结核病研究中的进展[J]. 结核与肺部疾病杂志, 2025, 6(1): 94-101. doi: 10.19983/j.issn.2096-8493.2024141

Yang Shuqi, Li Feng. Advances in PD1/PD-L1 inhibitors in tuberculosis research[J]. Journal of Tuberculosis and Lung Disease, 2025, 6(1): 94-101. doi: 10.19983/j.issn.2096-8493.2024141

图/表 2

参考文献 84

[1]	World Health Organization. Global tuberculosis report 2024. Geneva: World Health Organization, 2024.
[2]	Sakai S, Kauffman KD, Sallin MA, et al. CD4 T Cell-Derived IFN-γ Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal Disease. PLoS Pathog, 2016, 12(5): e1005667. doi:10.1371/journal.ppat.1005667.
[3]	Kamboj D, Gupta P, Basil MV, et al. Improved Mycobacterium tuberculosis clearance after the restoration of IFN-γ(+) TNF-α(+) CD4(+) T cells: Impact of PD-1 inhibition in active tuberculosis patients. Eur J Immunol, 2020, 50(5): 736-747. doi:10.1002/eji.201948283. pmid: 32113187
[4]	Hassan SS, Akram M, King EC, et al. PD-1, PD-L1 and PD-L 2 Gene Expression on T-Cells and Natural Killer Cells Declines in Conjunction with a Reduction in PD-1 Protein during the Intensive Phase of Tuberculosis Treatment. PLoS One, 2015, 10(9): e0137646. doi:10.1371/journal.pone.0137646.
[5]	Liu Q, Ou Q, Shen L, et al. BATF Potentially Mediates Nega-tive Regulation of PD-1/PD-Ls Pathway on T Cell Functions in Mycobacterium tuberculosis Infection. Front Immunol, 2019, 10: 2430. doi:10.3389/fimmu.2019.02430.
[6]	Shi CL, Zhang JP, Xu P, et al. Upregulation of PD-1 expression on circulating CD8⁺ but not CD4⁺ T cells is associated with tuberculosis infection in health care workers. BMC Immunol, 2021, 22(1): 39. doi:10.1186/s12865-021-00433-9.
[7]	Moslehi J, Lichtman AH, Sharpe AH, et al. Immune checkpoint inhibitor-associated myocarditis: manifestations and mechanisms. J Clin Invest, 2021, 131(5):e145186. doi:10.1172/JCI145186.
[8]	Srivastava S, Ernst JD. Cell-to-cell transfer of M.tuberculosis antigens optimizes CD4 T cell priming. Cell Host Microbe, 2014, 15(6): 741-752. doi:10.1016/j.chom.2014.05.007. pmid: 24922576
[9]	Li L, Qiao D, Fu X, et al. Identification of M.tuberculosis-specific Th 1 cells expressing CD69 generated in vivo in pleural fluid cells from patients with tuberculous pleurisy. PLoS One, 2011, 6(8): e23700. doi:10.1371/journal.pone.0023700.
[10]	Stephens R, Langhorne J. Effector memory Th1 CD4 T cells are maintained in a mouse model of chronic malaria. PLoS Pathog, 2010, 6(11): e1001208. doi:10.1371/journal.ppat.1001208.
[11]	Jankovic D, Feng CG. CD4(+) T Cell Differentiation in Infection: Amendments to the Th1/Th2 Axiom. Front Immunol, 2015, 6: 198. doi:10.3389/fimmu.2015.00198. pmid: 25972870
[12]	Parackova Z, Bloomfield M, Klocperk A, et al. Neutrophils mediate Th 17 promotion in COVID-19 patients. J Leukoc Biol, 2021, 109(1): 73-76. doi:10.1002/jlb.4covcra0820-481rrr.
[13]	Doz E, Lombard R, Carreras F, et al. Mycobacteria-infected dendritic cells attract neutrophils that produce IL-10 and specifically shut down Th 17 CD4 T cells through their IL-10 receptor. J Immunol, 2013, 191(7): 3818-3826. doi:10.4049/jimmunol.1300527.
[14]	Green AM, Difazio R, Flynn JL. IFN-γ from CD4 T cells is essential for host survival and enhances CD8 T cell function during Mycobacterium tuberculosis infection. J Immunol, 2013, 190(1): 270-277. doi:10.4049/jimmunol.1200061.
[15]	Yang Q, Qi F, Ye T, et al. The interaction of macrophages and CD 8 T cells in bronchoalveolar lavage fluid is associated with latent tuberculosis infection. Emerg Microbes Infect, 2023, 12(2): 2239940. doi:10.1080/22221751.2023.2239940.
[16]	Chowdhury A, Hayes TL, Bosinger SE, et al. Differential Impact of In Vivo CD8⁺ T Lymphocyte Depletion in Controller versus Progressor Simian Immunodeficiency Virus-Infected Macaques. J Virol, 2015, 89(17): 8677-8686. doi:10.1128/jvi.00869-15. pmid: 26063417
[17]	Carpenter SM, Behar M. A new vaccine for tuberculosis in rhesus macaques. Nat Med, 2018, 24(2): 124-126. doi:10.1038/nm.4488. pmid: 29414932
[18]	Sharan R, Singh DK, Rengarajan J, et al. Characterizing Early T Cell Responses in Nonhuman Primate Model of Tuberculosis. Front Immunol, 2021, 12: 706723. doi:10.3389/fimmu.2021.706723.
[19]	Bold TD, Ernst JD. CD4⁺ T cell-dependent IFN-γ production by CD8⁺ effector T cells in Mycobacterium tuberculosis infection. J Immunol, 2012, 189(5): 2530-2536. doi:10.4049/jimmunol.1200994.
[20]	Swanson RV, Gupta A, Foreman TW, et al. Antigen-specific B cells direct T follicular-like helper cells into lymphoid follicles to mediate Mycobacterium tuberculosis control. Nat Immunol, 2023, 24(5): 855-868. doi:10.1038/s41590-023-01476-3.
[21]	Jurado JO, Alvarez IB, Pasquinelli V, et al. Programmed death (PD) -1:PD-ligand 1/PD-ligand 2 pathway inhibits T cell effector functions during human tuberculosis. J Immunol, 2008, 181(1): 116-125. doi:10.4049/jimmunol.181.1.116.
[22]	Reungwetwattana T, Adjei AA. Anti-PD-1 Antibody Treatment and the Development of Acute Pulmonary Tuberculosis. J Thorac Oncol, 2016, 11(12): 2048-2050. doi:10.1016/j.jtho.2016.10.008. pmid: 27866633
[23]	Lentz RW, Colton MD, Mitra SS, et al. Innate Immune Checkpoint Inhibitors: The Next Breakthrough in Medical Oncology? Mol Cancer Ther, 2021, 20(6): 961-974. doi:10.1158/1535-7163.Mct-21-0041. pmid: 33850005
[24]	Heeke AL, Tan AR. Checkpoint inhibitor therapy for metastatic triple-negative breast cancer. Cancer Metastasis Rev, 2021, 40(2): 537-547. doi:10.1007/s10555-021-09972-4.
[25]	Lin PL, Rutledge T, Green AM, et al. CD4 T cell depletion exacerbates acute Mycobacterium tuberculosis while reactivation of latent infection is dependent on severity of tissue depletion in cynomolgus macaques. AIDS Res Hum Retroviruses, 2012, 28(12): 1693-1702. doi:10.1089/aid.2012.0028.
[26]	Kamphorst AO, Ahmed R. Manipulating the PD-1 pathway to improve immunity. Curr Opin Immunol, 2013, 25(3): 381-388. doi:10.1016/j.coi.2013.03.003. pmid: 23582509
[27]	Jiang J, Cao Z, Qu J, et al. PD-1-expressing MAIT cells from patients with tuberculosis exhibit elevated production of CXCL13. Scand J Immunol, 2020, 91(4): e12858. doi:10.1111/sji.12858.
[28]	Naimi A, Mohammed RN, Raji A, et al. Tumor immunothera-pies by immune checkpoint inhibitors (ICIs); the pros and cons. Cell Commun Signal, 2022, 20(1): 44. doi:10.1186/s12964-022-00854-y. pmid: 35392976
[29]	Shi J, Li J, Wang Q, et al. The safety and efficacy of immunotherapy with anti-programmed cell death 1 monoclonal antibody for lung cancer complicated with Mycobacterium tuberculosis infection. Transl Lung Cancer Res, 2021, 10(10): 3929-3942. doi:10.21037/tlcr-21-524.
[30]	Gordon SR, Maute RL, Dulken BW, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature, 2017, 545(7655): 495-499. doi:10.1038/nature22396.
[31]	Ahmed M, Tezera LB, Elkington PT, et al. The paradox of immune checkpoint inhibition re-activating tuberculosis. Eur Respir J, 2022, 60(5):2102512. doi:10.1183/13993003.02512-2021.
[32]	Geraud A, Gougis P, Vozy A, et al. Clinical Pharmacology and Interplay of Immune Checkpoint Agents: A Yin-Yang Balance. Annu Rev Pharmacol Toxicol, 2021, 61: 85-112. doi:10.1146/annurev-pharmtox-022820-093805.
[33]	Periasamy S, Dhiman R, Barnes PF, et al. Programmed death 1 and cytokine inducible SH2-containing protein dependent expansion of regulatory T cells upon stimulation With Mycobacterium tuberculosis. J Infect Dis, 2011, 203(9): 1256-1263. doi:10.1093/infdis/jir011.
[34]	Wykes MN, Lewin SR. Immune checkpoint blockade in infectious diseases. Nat Rev Immunol, 2018, 18(2): 91-104. doi:10.1038/nri.2017.112. pmid: 28990586
[35]	Mcgee MC, Zhang T, Mamazine N, et al. PD-1 and ICOS counter-regulate tissue resident regulatory T cell development and IL-10 production during flu. Front Immunol, 2022, 13: 984476. doi:10.3389/fimmu.2022.984476.
[36]	Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol, 2015, 15(8): 486-499. doi:10.1038/nri3862. pmid: 26205583
[37]	Okazaki T, Chikuma S, Iwai Y, et al. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol, 2013, 14(12): 1212-1218. doi:10.1038/ni.2762. pmid: 24240160
[38]	Collier JL, Weiss SA, Pauken KE, et al. Not-so-opposite ends of the spectrum: CD8(+) T cell dysfunction across chronic infection, cancer and autoimmunity. Nat Immunol, 2021, 22(7): 809-819. doi:10.1038/s41590-021-00949-7. pmid: 34140679
[39]	陈珍妍, 胡志东, 范小勇. 免疫检查点阻断在逆转慢性结核病T细胞耗竭中的应用. 生命科学, 2020, 32(4): 349-358. doi:10.13376/j.cbls/2020045.
[40]	Chen F, Qian WB, Chen ZH, et al. T cell exhaustion methyla-tion signature drives differential immune responses in glioblastoma. Discov Oncol, 2024, 15(1): 530. doi:10.1007/s12672-024-01412-3.
[41]	Zheng Y, Wang S, Cai J, et al. The progress of immune checkpoint therapy in primary liver cancer. Biochim Biophys Acta Rev Cancer, 2021, 1876(2): 188638. doi:10.1016/j.bbcan.2021.188638.
[42]	Khan N, Vidyarthi A, Amir M, et al. T-cell exhaustion in tuberculosis: pitfalls and prospects. Crit Rev Microbiol, 2017, 43(2): 133-141. doi:10.1080/1040841x.2016.1185603. pmid: 27800700
[43]	Ogishi M, Yang R, Aytekin C, et al. Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child. Nat Med, 2021, 27(9): 1646-1654. doi:10.1038/s41591-021-01388-5. pmid: 34183838
[44]	Nathan CF, Murray HW, Wiebe ME, et al. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med, 1983, 158(3): 670-689. doi:10.1084/jem.158.3.670. pmid: 6411853
[45]	Yao S, Huang D, Chen CY, et al. CD4⁺ T cells contain early extrapulmonary tuberculosis (TB) dissemination and rapid TB progression and sustain multieffector functions of CD8⁺ T and CD3- lymphocytes: mechanisms of CD4⁺ T cell immunity. J Immunol, 2014, 192(5): 2120-2132. doi:10.4049/jimmunol.1301373.
[46]	Anand K, Sahu G, Burns E, et al. Mycobacterial infections due to PD-1 and PD-L 1 checkpoint inhibitors. ESMO Open, 2020, 5(4). doi:10.1136/esmoopen-2020-000866.
[47]	Lázár-Molnár E, Chen B, Sweeney KA, et al. Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis. Proc Natl Acad Sci U S A, 2010, 107(30): 13402-13407. doi:10.1073/pnas.1007394107.
[48]	Jouanguy E, Lamhamed-Cherradi S, Altare F, et al. Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis. J Clin Invest, 1997, 100(11): 2658-2664. doi:10.1172/jci119810. pmid: 9389728
[49]	Suarez GV, Melucci Ganzarain CDC, Vecchione MB, et al. PD-1/PD-L 1 Pathway Modulates Macrophage Susceptibility to Mycobacterium tuberculosis Specific CD8(+) T cell Induced Death. Sci Rep, 2019, 9(1): 187. doi:10.1038/s41598-018-36403-2.
[50]	Russell SL, Lamprechi DA, Mandizvo T, et al. Compromised Metabolic Reprogramming Is an Early Indicator of CD8(+) T Cell Dysfunction during Chronic Mycobacterium tuberculosis Infection. Cell Rep, 2019, 29(11): 3564-3579.e5. doi:10.1016/j.celrep.2019.11.034.
[51]	Grotzke JE, Lewinsohn DM. Role of CD8⁺ T lymphocytes in control of Mycobacterium tuberculosis infection. Microbes Infect, 2005, 7(4): 776-788. doi:10.1016/j.micinf.2005.03.001. pmid: 15823514
[52]	Bengsch B, Johnson AL, Kurachi M, et al. Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion. Immunity, 2016, 45(2): 358-373. doi:10.1016/j.immuni.2016.07.008. pmid: 27496729
[53]	Xiong K, Sun W, He Y, et al. Advances in molecular mechanisms of interaction between Mycobacterium tuberculosis and lung cancer: a narrative review. Transl Lung Cancer Res, 2021, 10(10): 4012-4026. doi:10.21037/tlcr-21-465.
[54]	Barber DL, Sakai S, Kudchadkar RR, et al. Tuberculosis following PD-1 blockade for cancer immunotherapy. Sci Transl Med, 2019, 11(475). doi:10.1126/scitranslmed.aat2702.
[55]	Day CL, Abrahams DA, Bujun R, et al. PD-1 Expression on Mycobacterium tuberculosis-Specific CD 4 T Cells Is Associated With Bacterial Load in Human Tuberculosis. Front Immunol, 2018, 9: 1995. doi:10.3389/fimmu.2018.01995.
[56]	Singh A, Mohan A, Dey AB, et al. Inhibiting the programmed death 1 pathway rescues Mycobacterium tuberculosis-specific interferon γ-producing T cells from apoptosis in patients with pulmonary tuberculosis. J Infect Dis, 2013, 208(4): 603-615. doi:10.1093/infdis/jit206. pmid: 23661793
[57]	Tezera LB, Bielecka MK, Ogongo P, et al. Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-α. Elife, 2020, 9. doi:10.7554/eLife.52668.
[58]	Abers MS, Lionakis MS, Kontoyiannis DP. Checkpoint Inhibition and Infectious Diseases: A Good Thing? Trends Mol Med, 2019, 25(12): 1080-1093. doi:10.1016/j.molmed.2019.08.004. pmid: 31494023
[59]	Dyck L, Mills KHG. Immune checkpoints and their inhibition in cancer and infectious diseases. Eur J Immunol, 2017, 47(5): 765-779. doi:10.1002/eji.201646875. pmid: 28393361
[60]	Stephens-Victor E, Sharma VK, Das M, et al. IL-1β, But Not Programed Death-1 and Programed Death Ligand Pathway, Is Critical for the Human Th17 Response to Mycobacterium tuberculosis. Front Immunol, 2016, 7: 465. doi:10.3389/fimmu.2016.00465.
[61]	Pan SW, Shu CC, Huang JR, et al. PD-L1 Expression in Monocytes Correlates with Bacterial Burden and Treatment Outcomes in Active Pulmonary Tuberculosis. Int J Mol Sci, 2022, 23(3):1619. doi:10.3390/ijms23031619.
[62]	Bickett TE, Karam SD. Tuberculosis-Cancer Parallels in Immune Response Regulation. Int J Mol Sci, 2020, 21(17):6136. doi:10.3390/ijms21176136.
[63]	Moguche AO, Musvosvi M, Penn-Nicholson A, et al. Antigen Availability Shapes T Cell Differentiation and Function during Tuberculosis. Cell Host Microbe, 2017, 21(6): 695-706.e5. doi:10.1016/j.chom.2017.05.012. pmid: 28618268
[64]	Shen L, Gao Y, Liu Y, et al. PD-1/PD-L pathway inhibits M.tb-specific CD4(+) T-cell functions and phagocytosis of macrophages in active tuberculosis. Sci Rep, 2016, 6: 38362. doi:10.1038/srep38362. pmid: 27924827
[65]	Cao S, Li J, Lu J, et al. Mycobacterium tuberculosis antigens repress Th 1 immune response suppression and promotes lung cancer metastasis through PD-1/PDl-1 signaling pathway. Cell Death Dis, 2019, 10(2): 44. doi:10.1038/s41419-018-1237-y.
[66]	Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet, 2021, 398(10304): 1002-1014. doi:10.1016/s0140-6736(21)01206-x. pmid: 34509219
[67]	Salas-benito D, Pérez-gracia JL, Ponz-sarvisé M, et al. Paradigms on Immunotherapy Combinations with Chemotherapy. Cancer Discov, 2021, 11(6): 1353-1367. doi:10.1158/2159-8290.Cd-20-1312. pmid: 33712487
[68]	Sundar R, Cho BC, Brahmer JR, et al. Nivolumab in NSCLC: latest evidence and clinical potential. Ther Adv Med Oncol, 2015, 7(2): 85-96. doi:10.1177/1758834014567470. pmid: 25755681
[69]	Stroh GR, Peikert T, Escalante P. Active and latent tuberculosis infections in patients treated with immune checkpoint inhibitors in a non-endemic tuberculosis area. Cancer Immunol Immunother, 2021, 70(11): 3105-3111. doi:10.1007/s00262-021-02905-8. pmid: 33770211
[70]	金文婷, 倪佳依, 胡必杰, 等. 免疫检查点抑制剂相关结核病:1例报道及文献分析. 复旦学报(医学版), 2024, 51(2): 272-276 doi:10.3969/j.issn.1672-8467.2024.02.020.
[71]	任坦坦, 詹森林, 王玉香, 等. PD-1/PD-L1抑制剂相关活动性结核病的临床特点及文献复习. 结核与肺部疾病杂志, 2023, 4(1): 27-32. doi:10.19983/j.issn.2096-8493.20220161.
[72]	Barber DL, Mayer-barber KD, FENG CG, et al. CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J Immunol, 2011, 186(3): 1598-1607. doi:10.4049/jimmunol.1003304. pmid: 21172867
[73]	Tousif S, Singh Y, Prasad DV, et al. T cells from Programmed Death-1 deficient mice respond poorly to Mycobacterium tuberculosis infection. PLoS One, 2011, 6(5): e19864. doi:10.1371/journal.pone.0019864.
[74]	Fujita K, Terashima T, Mio T. Anti-PD1 Antibody Treatment and the Development of Acute Pulmonary Tuberculosis. J Thorac Oncol, 2016, 11(12): 2238-2240. doi:10.1016/j.jtho.2016.07.006. pmid: 27423391
[75]	Lee JJ, Chan A, Tang T. Tuberculosis reactivation in a patient receiving anti-programmed death-1 (PD-1) inhibitor for relapsed Hodgkin’s lymphoma. Acta Oncol, 2016, 55(4): 519-520. doi:10.3109/0284186x.2015.1125017.
[76]	Chu YC, Fang KC, Chen HC, et al. Pericardial Tamponade Caused by a Hypersensitivity Response to Tuberculosis Reactivation after Anti-PD-1 Treatment in a Patient with Advanced Pulmonary Adenocarcinoma. J Thorac Oncol, 2017, 12(8): e111-e114. doi:10.1016/j.jtho.2017.03.012.
[77]	Shen BJ, Lin HH. Time-dependent association between cancer and risk of tuberculosis: A population-based cohort study. Int J Infect Dis, 2021, 108: 340-346. doi:10.1016/j.ijid.2021.05.037.
[78]	Picchi H, Mateus C, Chouaid C, et al. Infectious complications associated with the use of immune checkpoint inhibitors in oncology: reactivation of tuberculosis after anti PD-1 treatment. Clin Microbiol Infect, 2018, 24(3): 216-218. doi:10.1016/j.cmi.2017.12.003.
[79]	Anastasopoulou A, Ziogas DC, Samarkos M, et al. Reactivation of tuberculosis in cancer patients following administration of immune checkpoint inhibitors: current evidence and clinical practice recommendations. J Immunother Cancer, 2019, 7(1): 239. doi:10.1186/s40425-019-0717-7. pmid: 31484550
[80]	Hamashima R, Uchino J, Morimoto Y, et al. Association of immune checkpoint inhibitors with respiratory infections: A review. Cancer Treat Rev, 2020, 90: 102109. doi:10.1016/j.ctrv.2020.102109.
[81]	Müller M, Wander S, Colebunders R, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis, 2010, 10(4): 251-261. doi:10.1016/s1473-3099(10)70026-8. pmid: 20334848
[82]	Granier C, Dariane C, COMBE P, et al. Tim-3 Expression on Tumor-Infiltrating PD-1(+)CD8(+) T Cells Correlates with Poor Clinical Outcome in Renal Cell Carcinoma. Cancer Res, 2017, 77(5): 1075-1082. doi:10.1158/0008-5472.Can-16-0274.
[83]	Zhou Q, Munger ME, Veenstra RG, et al. Coexpression of Tim-3 and PD-1 identifies a CD8⁺ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood, 2011, 117(17): 4501-4510. doi:10.1182/blood-2010-10-310425.
[84]	Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8⁺ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol, 2009, 10(1): 29-37. doi:10.1038/ni.1679. pmid: 19043418

项目	Fujita等^[74]	Lee等^[75]	Chu等^[76]
基本情况	患者,72岁,男性	患者,87岁,男性	患者,59岁,男性
癌症类型	非小细胞肺癌	结节性硬化型霍奇金淋巴瘤	肺腺癌
PD-1/PD-L1抑制剂	纳武利尤单抗	帕博利珠单抗	纳武利尤单抗
治疗周期	8个周期	5个周期	3个周期
不良反应事件	新的异常阴影	发热、体质量减轻	心包填塞
检测结核病的方式	IGRA阳性	痰培养阳性	心包积液培养发现结核分枝杆菌