中国癌症杂志 ›› 2023, Vol. 33 ›› Issue (12): 1083-1091.doi: 10.19401/j.cnki.1007-3639.2023.12.003
收稿日期:
2023-08-17
修回日期:
2023-10-24
出版日期:
2023-12-30
发布日期:
2023-12-28
通信作者:
毕 楠(ORCID: 0000-0001-7201-2930),主任医师。
作者简介:
王 妤(ORCID: 0009-0008-1769-9387),在读博士研究生,住院医师。
Received:
2023-08-17
Revised:
2023-10-24
Published:
2023-12-30
Online:
2023-12-28
Contact:
BI Nan
文章分享
摘要:
既往观点认为,放射治疗主要通过破坏肿瘤细胞脱氧核糖核酸双链直接发挥杀伤肿瘤细胞的作用,近年来研究发现,放疗也可通过上调局部与全身免疫反应,间接产生积极有效的抗肿瘤免疫应答。然而,放疗的免疫调节效应具有双面性,一方面可激活并产生抗肿瘤免疫促进效应,另一方面也可能产生免疫抑制作用。其中,放疗正向调节适应性与固有性抗肿瘤免疫反应的关键分子机制主要包括:诱导免疫原性细胞凋亡从而促进T淋巴细胞的增殖与活化;激活环磷酸鸟苷-腺苷合成酶-干扰素基因刺激蛋白通路引发Ⅰ型干扰素反应;改变肿瘤细胞表型,加强其免疫原性与抗原可视度;刺激肿瘤细胞与基质细胞释放多种炎症因子,重塑肿瘤免疫微环境;上调肿瘤细胞表面免疫检查点以及死亡受体等的表达,促进免疫识别与抗肿瘤免疫应答。而放疗负向抑制免疫反应的主要机制包括:诱导肿瘤细胞上调多种免疫抑制因子的基因表达;增强包括调节性T细胞、髓系来源抑制性细胞在内的多种免疫抑制细胞的功能与作用;导致淋巴细胞的数量减少以及免疫效应细胞的耗竭等。基于以上关于放疗免疫调节效应的机制原理探索,目前在放疗联合免疫治疗的临床实践中也显示出重大的研究进展,包括免疫治疗时代背景下的放疗远隔效应,即放疗照射野以外产生的有效抗肿瘤免疫应答,以及立体定向放疗或低剂量放疗联合免疫检查点抑制剂治疗时显著增加的疗效获益。然而,目前对于放疗联合免疫治疗产生的协同作用机制及其具体影响因素等仍不明确,未来需要在放疗与免疫治疗联合治疗的最佳放疗剂量、放疗分割模式、放疗照射部位与靶区设计、免疫药物选择以及放疗与免疫联合治疗顺序等研究方向开展深入探索,以进一步提高临床疗效,促进放疗免疫调节生物学效应的临床转化应用。本文将对放疗的免疫调节效应以及放疗与免疫治疗联合协同作用的基础与临床研究最新进展进行系统综述,以期为放疗联合免疫治疗的理论基础发展与临床实践进步提供参考。
中图分类号:
王妤, 毕楠. 放疗免疫调节效应研究的进展——从基础到临床[J]. 中国癌症杂志, 2023, 33(12): 1083-1091.
WANG Yu, BI Nan. Advancements in the research of immunomodulatory effects of radiation therapy: from basic to clinical[J]. China Oncology, 2023, 33(12): 1083-1091.
[1] |
KORNEPATI A V R, ROGERS C M, SUNG P, et al. The complementarity of DDR, nucleic acids and anti-tumour immunity[J]. Nature, 2023, 619(7970): 475-486.
doi: 10.1038/s41586-023-06069-6 |
[2] |
MCLAUGHLIN M, PATIN E C, PEDERSEN M, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy[J]. Nat Rev Cancer, 2020, 20(4): 203-217.
doi: 10.1038/s41568-020-0246-1 pmid: 32161398 |
[3] | HUANG R X, ZHOU P K. DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer[J]. Signal Transduct Target Ther, 2020, 5(1): 60. |
[4] | ZHANG Z F, LIU X, CHEN D W, et al. Radiotherapy combined with immunotherapy: the dawn of cancer treatment[J]. Signal Transduct Target Ther, 2022, 7(1): 258. |
[5] |
GALLUZZI L, VITALE I, WARREN S, et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death[J]. J Immunother Cancer, 2020, 8(1): e000337.
doi: 10.1136/jitc-2019-000337 |
[6] |
FUCIKOVA J, KEPP O, KASIKOVA L, et al. Detection of immunogenic cell death and its relevance for cancer therapy[J]. Cell Death Dis, 2020, 11(11): 1013.
doi: 10.1038/s41419-020-03221-2 pmid: 33243969 |
[7] |
O’DONNELL J S, TENG M W L, SMYTH M J. Cancer immunoediting and resistance to T cell-based immunotherapy[J]. Nat Rev Clin Oncol, 2019, 16(3): 151-167.
doi: 10.1038/s41571-018-0142-8 pmid: 30523282 |
[8] |
VORONOVA V, VISLOBOKOVA A, MUTIG K, et al. Combination of immune checkpoint inhibitors with radiation therapy in cancer: a hammer breaking the wall of resistance[J]. Front Oncol, 2022, 12: 1035884.
doi: 10.3389/fonc.2022.1035884 |
[9] |
LI W, YANG J, LUO L H, et al. Targeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death[J]. Nat Commun, 2019, 10(1): 3349.
doi: 10.1038/s41467-019-11269-8 pmid: 31350406 |
[10] |
MA Y C, ZHANG Y X, LI X Q, et al. Near-infrared Ⅱ phototherapy induces deep tissue immunogenic cell death and potentiates cancer immunotherapy[J]. ACS Nano, 2019, 13(10): 11967-11980.
doi: 10.1021/acsnano.9b06040 |
[11] |
HAYASHI K, NIKOLOS F, LEE Y C, et al. Tipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death[J]. Nat Commun, 2020, 11(1): 6299.
doi: 10.1038/s41467-020-19970-9 pmid: 33288764 |
[12] |
AHMED A, TAIT S W G. Targeting immunogenic cell death in cancer[J]. Mol Oncol, 2020, 14(12): 2994-3006.
doi: 10.1002/1878-0261.12851 pmid: 33179413 |
[13] |
MUIRE P J, SCHWACHA M G, WENKE J C. Systemic T cell exhaustion dynamics is linked to early high mobility group box protein 1 (HMGB1) driven hyper-inflammation in a polytrauma rat model[J]. Cells, 2021, 10(7): 1646.
doi: 10.3390/cells10071646 |
[14] |
DE MARTINO M, DAVIAUD C, VANPOUILLE-BOX C. Radiotherapy: an immune response modifier for immuno-oncology[J]. Semin Immunol, 2021, 52: 101474.
doi: 10.1016/j.smim.2021.101474 |
[15] |
YAN C H, MA X X, GUO Z B, et al. Time-spatial analysis of T cell receptor repertoire in esophageal squamous cell carcinoma patients treated with combined radiotherapy and PD-1 blockade[J]. Oncoimmunology, 2022, 11(1): 2025668.
doi: 10.1080/2162402X.2022.2025668 |
[16] |
FANG L, HAO Y, YU H H, et al. Methionine restriction promotes cGAS activation and chromatin untethering through demethylation to enhance antitumor immunity[J]. Cancer Cell, 2023, 41(6): 1118-1133.e12.
doi: 10.1016/j.ccell.2023.05.005 pmid: 37267951 |
[17] |
CAROZZA J A, BÖHNERT V, NGUYEN K C, et al. Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity[J]. Nat Cancer, 2020, 1(2): 184-196.
doi: 10.1038/s43018-020-0028-4 |
[18] |
GARLAND K M, SHEEHY T L, WILSON J T. Chemical and biomolecular strategies for STING pathway activation in cancer immunotherapy[J]. Chem Rev, 2022, 122(6): 5977-6039.
doi: 10.1021/acs.chemrev.1c00750 pmid: 35107989 |
[19] | LONG Y, GUO J X, CHEN J L, et al. GPR162 activates STING dependent DNA damage pathway as a novel tumor suppressor and radiation sensitizer[J]. Signal Transduct Target Ther, 2023, 8(1): 48. |
[20] |
MOTWANI M, PESIRIDIS S, FITZGERALD K A. DNA sensing by the cGAS-STING pathway in health and disease[J]. Nat Rev Genet, 2019, 20(11): 657-674.
doi: 10.1038/s41576-019-0151-1 pmid: 31358977 |
[21] |
DU S S, CHEN G W, YANG P, et al. Radiation therapy promotes hepatocellular carcinoma immune cloaking via PD-L1 upregulation induced by cGAS-STING activation[J]. Int J Radiat Oncol Biol Phys, 2022, 112(5): 1243-1255.
doi: 10.1016/j.ijrobp.2021.12.162 |
[22] |
CHIN E N, SULPIZIO A, LAIRSON L L. Targeting STING to promote antitumor immunity[J]. Trends Cell Biol, 2023, 33(3): 189-203.
doi: 10.1016/j.tcb.2022.06.010 |
[23] |
DHATCHINAMOORTHY K, COLBERT J D, ROCK K L. Cancer immune evasion through loss of MHC class Ⅰ antigen presentation[J]. Front Immunol, 2021, 12: 636568.
doi: 10.3389/fimmu.2021.636568 |
[24] |
YAMAMOTO K, VENIDA A, YANO J, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I[J]. Nature, 2020, 581(7806): 100-105.
doi: 10.1038/s41586-020-2229-5 |
[25] |
JIN W J, ZANGL L M, HYUN M, et al. ATM inhibition augments type Ⅰ interferon response and antitumor T-cell immunity when combined with radiation therapy in murine tumor models[J]. J Immunother Cancer, 2023, 11(9): e007474.
doi: 10.1136/jitc-2023-007474 |
[26] |
ZENG H, ZHANG W J, GONG Y, et al. Radiotherapy activates autophagy to increase CD8+ T cell infiltration by modulating major histocompatibility complex class-I expression in non-small cell lung cancer[J]. J Int Med Res, 2019, 47(8): 3818-3830.
doi: 10.1177/0300060519855595 |
[27] |
LIN W Z, XU Y Y, CHEN X C, et al. Radiation-induced small extracellular vesicles as “carriages” promote tumor antigen release and trigger antitumor immunity[J]. Theranostics, 2020, 10(11): 4871-4884.
doi: 10.7150/thno.43539 |
[28] |
SEYEDIN S N, HASIBUZZAMAN M M, PHAM V, et al. Combination therapy with radiation and PARP inhibition enhances responsiveness to anti-PD-1 therapy in colorectal tumor models[J]. Int J Radiat Oncol Biol Phys, 2020, 108(1): 81-92.
doi: 10.1016/j.ijrobp.2020.01.030 |
[29] | LIU C, LI X H, HUANG Q Y, et al. Single-cell RNA-sequencing reveals radiochemotherapy-induced innate immune activation and MHC-Ⅱ upregulation in cervical cancer[J]. Signal Transduct Target Ther, 2023, 8(1): 44. |
[30] |
LIU S B, WANG W K, HU S Y, et al. Radiotherapy remodels the tumor microenvironment for enhancing immunotherapeutic sensitivity[J]. Cell Death Dis, 2023, 14(10): 679.
doi: 10.1038/s41419-023-06211-2 pmid: 37833255 |
[31] |
WANG Y F, LIU Z G, YUAN H F, et al. The reciprocity between radiotherapy and cancer immunotherapy[J]. Clin Cancer Res, 2019, 25(6): 1709-1717.
doi: 10.1158/1078-0432.CCR-18-2581 pmid: 30413527 |
[32] |
REN J L, LI L L, YU B F, et al. Extracellular vesicles mediated proinflammatory macrophage phenotype induced by radiotherapy in cervical cancer[J]. BMC Cancer, 2022, 22(1): 88.
doi: 10.1186/s12885-022-09194-z pmid: 35062905 |
[33] |
ZHAI D Y, AN D D, WAN C, et al. Radiotherapy: brightness and darkness in the era of immunotherapy[J]. Transl Oncol, 2022, 19: 101366.
doi: 10.1016/j.tranon.2022.101366 |
[34] |
SUN L J, KEES T, ALMEIDA A S, et al. Activating a collaborative innate-adaptive immune response to control metastasis[J]. Cancer Cell, 2021, 39(10): 1361-1374.e9.
doi: 10.1016/j.ccell.2021.08.005 pmid: 34478639 |
[35] |
RODRIGUEZ-RUIZ M E, VITALE I, HARRINGTON K J, et al. Immunological impact of cell death signaling driven by radiation on the tumor microenvironment[J]. Nat Immunol, 2020, 21(2): 120-134.
doi: 10.1038/s41590-019-0561-4 |
[36] |
STANISZEWSKA M, IKING J, LÜCKERATH K, et al. Drug and molecular radiotherapy combinations for metastatic castration resistant prostate cancer[J]. Nucl Med Biol, 2021, 96/97: 101-111.
doi: 10.1016/j.nucmedbio.2021.03.009 |
[37] |
YU J L, GREEN M D, LI S S, et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination[J]. Nat Med, 2021, 27(1): 152-164.
doi: 10.1038/s41591-020-1131-x pmid: 33398162 |
[38] |
KUMAR V, BAUER C, STEWART J H 4th. Cancer cell-specific cGAS/STING signaling pathway in the era of advancing cancer cell biology[J]. Eur J Cell Biol, 2023, 102(3): 151338.
doi: 10.1016/j.ejcb.2023.151338 |
[39] |
BOUKHALED G M, HARDING S, BROOKS D G. Opposing roles of type Ⅰ interferons in cancer immunity[J]. Annu Rev Pathol, 2021, 16: 167-198.
doi: 10.1146/pathmechdis.2021.16.issue-1 |
[40] |
BENCI J L, XU B H, QIU Y, et al. Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade[J]. Cell, 2016, 167(6): 1540-1554.e12.
doi: S0092-8674(16)31594-X pmid: 27912061 |
[41] |
WU Y, SONG Y Q, WANG R Z, et al. Molecular mechanisms of tumor resistance to radiotherapy[J]. Mol Cancer, 2023, 22(1): 96.
doi: 10.1186/s12943-023-01801-2 pmid: 37322433 |
[42] |
NOZAWA H, TAIRA T, SONODA H, et al. Enhancement of radiation therapy by indoleamine 2, 3 dioxygenase 1 inhibition through multimodal mechanisms[J]. BMC Cancer, 2023, 23(1): 62.
doi: 10.1186/s12885-023-10539-5 |
[43] |
LIU M, LI Z Y, YAO W R, et al. IDO inhibitor synergized with radiotherapy to delay tumor growth by reversing T cell exhaustion[J]. Mol Med Rep, 2020, 21(1): 445-453.
doi: 10.3892/mmr.2019.10816 pmid: 31746428 |
[44] |
WEICHSELBAUM R R, LIANG H, DENG L F, et al. Radiotherapy and immunotherapy: a beneficial liaison?[J]. Nat Rev Clin Oncol, 2017, 14(6): 365-379.
doi: 10.1038/nrclinonc.2016.211 pmid: 28094262 |
[45] |
MONDINI M, LOYHER P L, HAMON P, et al. CCR2-dependent recruitment of tregs and monocytes following radiotherapy is associated with TNFα-mediated resistance[J]. Cancer Immunol Res, 2019, 7(3): 376-387.
doi: 10.1158/2326-6066.CIR-18-0633 pmid: 30696630 |
[46] |
PERSA E, BALOGH A, SÁFRÁNY G, et al. The effect of ionizing radiation on regulatory T cells in health and disease[J]. Cancer Lett, 2015, 368(2): 252-261.
doi: 10.1016/j.canlet.2015.03.003 pmid: 25754816 |
[47] |
WANG J Y, ZHAO X Q, WAN Y Y. Intricacies of TGF-β signaling in Treg and Th17 cell biology[J]. Cell Mol Immunol, 2023, 20(9): 1002-1022.
doi: 10.1038/s41423-023-01036-7 pmid: 37217798 |
[48] |
BRANDMAIER A, FORMENTI S C. The impact of radiation therapy on innate and adaptive tumor immunity[J]. Semin Radiat Oncol, 2020, 30(2): 139-144.
doi: S1053-4296(19)30080-3 pmid: 32381293 |
[49] |
CORTIULA F, REYMEN B, PETERS S, et al. Immunotherapy in unresectable stage Ⅲ non-small cell lung cancer: state of the art and novel therapeutic approaches[J]. Ann Oncol, 2022, 33(9): 893-908.
doi: 10.1016/j.annonc.2022.06.013 |
[50] |
YOSHIDA K, FRENCH B, YOSHIDA N, et al. Radiation exposure and longitudinal changes in peripheral monocytes over 50 years: the adult health study of atomic-bomb survivors[J]. Br J Haematol, 2019, 185(1): 107-115.
doi: 10.1111/bjh.2019.185.issue-1 |
[51] |
LAW A W, MOLE R H. Direct and abscopal effects of X-radiation on the thymus of the weanling rat[J]. Int J Radiat Biol Relat Stud Phys Chem Med, 1961, 3: 233-248.
pmid: 13759646 |
[52] |
POSTOW M A, CALLAHAN M K, BARKER C A, et al. Immunologic correlates of the abscopal effect in a patient with melanoma[J]. N Engl J Med, 2012, 366(10): 925-931.
doi: 10.1056/NEJMoa1112824 |
[53] |
GOLDEN E B, CHHABRA A, CHACHOUA A, et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial[J]. Lancet Oncol, 2015, 16(7): 795-803.
doi: 10.1016/S1470-2045(15)00054-6 pmid: 26095785 |
[54] |
SHAVERDIAN N, LISBERG A E, BORNAZYAN K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial[J]. Lancet Oncol, 2017, 18(7): 895-903.
doi: 10.1016/S1470-2045(17)30380-7 |
[55] |
THEELEN W S M E, PEULEN H M U, LALEZARI F, et al. Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial[J]. JAMA Oncol, 2019, 5(9): 1276-1282.
doi: 10.1001/jamaoncol.2019.1478 |
[56] |
THEELEN W S M E, CHEN D W, VERMA V, et al. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials[J]. Lancet Respir Med, 2021, 9(5): 467-475.
doi: 10.1016/S2213-2600(20)30391-X |
[57] |
FORMENTI S C, RUDQVIST N P, GOLDEN E, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade[J]. Nat Med, 2018, 24(12): 1845-1851.
doi: 10.1038/s41591-018-0232-2 pmid: 30397353 |
[58] |
CHEN Y, GAO M, HUANG Z Q, et al. SBRT combined with PD-1/PD-L1 inhibitors in NSCLC treatment: a focus on the mechanisms, advances, and future challenges[J]. J Hematol Oncol, 2020, 13(1): 105.
doi: 10.1186/s13045-020-00940-z |
[59] |
HERRERA F G, RONET C, OCHOA DE OLZA M, et al. Low-dose radiotherapy reverses tumor immune desertification and resistance to immunotherapy[J]. Cancer Discov, 2022, 12(1): 108-133.
doi: 10.1158/2159-8290.CD-21-0003 |
[60] |
PATEL R B, HERNANDEZ R, CARLSON P, et al. Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade[J]. Sci Transl Med, 2021, 13(602): eabb3631.
doi: 10.1126/scitranslmed.abb3631 |
[61] |
BARSOUMIAN H B, RAMAPRIYAN R, YOUNES A I, et al. Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma[J]. J Immunother Cancer, 2020, 8(2): e000537.
doi: 10.1136/jitc-2020-000537 |
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