The mechanism and clinical research progress on radiotherapy combined with immunotherapy in esophageal cancer
Gao Linrui, Xiao Zefen
Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Abstract：Radiation therapy (RT) is one of main methods of comprehensive treatment of esophageal cancer (EC). It plays a dual role in the immune system and can activate systemic immune response. However, the effect of tumor cytotoxicity induced by RT is limited, and it can induce abscopal effect in combination with immunotherapy (IT). A number of clinical studies have shown the effect and great potential of immune checkpoint inhibitors (ICIs), such as PD-1/L1 antibodies in advanced EC. Besides, RT and ICIs exert a synergistic effect. Currently, multiple ongoing studies related to concurrent radiochemotherapy combined with IT is expected to determine the efficacy of this comprehensive treatment in EC and elucidate the efficiency and cost-effectiveness.
Gao Linrui,Xiao Zefen. The mechanism and clinical research progress on radiotherapy combined with immunotherapy in esophageal cancer[J]. Chinese Journal of Radiation Oncology, 2022, 31(5): 462-467.
[1] Frey B, Gaipl US. Radio-immunotherapy:the focused beam expands[J]. Lancet Oncol, 2015, 16(7):742-743. DOI:10.1016/S1470-2045(15)00055-8. [2] Gajewski TF. The next hurdle in cancer immunotherapy:overcoming the non-T-cell-inflamed tumor microenvironment[J]. Semin Oncol, 2015, 42(4):663-671. DOI:10.1053/j.seminoncol.2015.05.011. [3] Jiang W, Chan CK, Weissman IL, et al. Immune priming of the tumor microenvironment by radiation[J]. Trends Cancer, 2016, 2(11):638-645. DOI:10.1016/j.trecan.2016.09.007. [4] Pu N, Zhao G, Gao S, et al. Neutralizing tgf-β promotes anti-tumor immunity of dendritic cells against pancreatic cancer by regulating T lymphocytes[J]. Cent Eur J Immunol, 2018, 43(2):123-131. DOI:10.5114/ceji.2018.77381. [5] Lauber K, Ernst A, Orth M, et al. Dying cell clearance and its impact on the outcome of tumor radiotherapy[J]. Front Oncol, 2012, 2:116. DOI:10.3389/fonc.2012.00116. [6] Ma JL, Jin L, Li YD, et al. The intensity of radiotherapy-elicited immune response is associated with esophageal cancer clearance[J]. J Immunol Res, 2014, 2014:794249. DOI:10.1155/2014/794249. [7] 郑荣寿, 孙可欣, 张思维, 等. 2015年中国恶性肿瘤流行情况分析[J]. 中华肿瘤杂志,2019,41(1):19-28. DOI:10.3760/cma.j.issn.0253-3766.2019.01.005. Zheng RS, Sun KX, Zhang SW, et al. Report of cancer epidemiology in China, 2015[J]. Chin J Oncol, 2019,41(1):19-28. DOI:10.3760/cma.j.issn.0253-3766.2019.01.005. [8] Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer:long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group[J]. JAMA, 1999. 281(17):1623-1627. DOI:10.1001/jama.281.17.1623. [9] Mirzaei HR, Rodriguez A, Shepphird J, et al. Chimeric antigen receptors T cell therapy in solid tumor:challenges and clinical applications[J]. Front Immunol, 2017, 8:1850. DOI:10.3389/fimmu.2017.01850. [10] Eriksson D, Stigbrand T. Radiation-induced cell death mechanisms[J]. Tumour Biol, 2010, 31(4):363-372. DOI:10.1007/s13277-010-0042-8. [11] Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation[J]. Nature, 2015, 517(7534):311-320. DOI:10.1038/nature14191. [12] Solinas G, Germano G, Mantovani A, et al. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation[J]. J Leukoc Biol, 2009, 86(5):1065-1073. DOI:10.1189/jlb.0609385. [13] Large M, Hehlgans S, Reichert S, et al. Study of the anti-inflammatory effects of low-dose radiation:the contribution of biphasic regulation of the antioxidative system in endothelial cells[J]. Strahlenther Onkol, 2015, 191(9):742-749. DOI:10.1007/s00066-015-0848-9. [14] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy[J]. Nat Rev Cancer, 2012, 12(4):252-264. DOI:10.1038/nrc3239. [15] Frey B, Rubner Y, Wunderlich R, et al. Induction of abscopal anti-tumor immunity and immunogenic tumor cell death by ionizing irradiation-implications for cancer therapies[J]. Curr Med Chem, 2012, 19(12):1751-1764. DOI:10.2174/092986712800099811. [16] Mandal P, Berger SB, Pillay S, et al. Rip3 induces apoptosis independent of pronecrotic kinase activity[J]. Mol Cell, 2014, 56(4):481-495. DOI:10.1016/j.molcel.2014.10.021. [17] Gajewski TF. The next hurdle in cancer immunotherapy:overcoming the non-T-cell-inflamed tumor microenvironment[J]. Semin Oncol, 2015, 42(4):663-671. DOI:10.1053/j.seminoncol.2015.05.011. [18] Frey B, Rubner Y, Kulzer L, et al. Antitumor immune responses induced by ionizing irradiation and further immune stimulation[J]. Cancer Immunol Immunother, 2014, 63(1):29-36. DOI:10.1007/s00262-013-1474-y. [19] Gaipl US, Multhoff G, Scheithauer H, et al. Kill and spread the word:stimulation of antitumor immune responses in the context of radiotherapy[J]. Immunotherapy, 2014, 6(5):597-610. DOI:10.2217/imt.14.38. [20] Kaminski JM, Shinohara E, Summers JB, et al. The controversial abscopal effect[J]. Cancer Treat Rev, 2005, 31(3):159-172. DOI:10.1016/j.ctrv.2005.03.004. [21] Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody[J]. Clin Cancer Res, 2009, 15(17):5379-5388. DOI:10.1158/1078-0432.CCR-09-0265. [22] Demaria S, Ng B, Devitt ml, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated[J]. Int J Radiat Oncol Biol Phys, 2004, 58(3):862-870. DOI:10.1016/j.ijrobp.2003.09.012. [23] Jürgenliemk-Schulz IM, Renes IB, Rutgers DH, et al. Anti-tumor effects of local irradiation in combination with peritumoral aDministration of low doses of recombinant interleukin-2(rIL-2)[J]. Radiat Oncol Investig, 1997, 5(2):54-61.DOI: 10.1002/(SICI)1520-6823(1997)5:2<54::AID-ROI3>3.0.CO;2-1. [24] Derer A, Deloch L, Rubner Y, et al. Radio-immunotherapy-induced immunogenic cancer cells as basis for induction of systemic anti-tumor immune responses-pre-clinical evidence and ongoing clinical applications[J]. Front Immunol, 2015, 6:505. DOI:10.3389/fimmu.2015.00505. [25] Golden EB, 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. [26] van de Laar L, Coffer PJ, Woltman AM. Regulation of dendritic cell development by GM-CSF:molecular control and implications for immune homeostasis and therapy[J]. Blood, 2012, 119(15):3383-3393. DOI:10.1182/blood-2011-11-370130. [27] Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade[J]. Proc Natl Acad Sci U S A, 2002, 99(19):12293-12297. DOI:10.1073/pnas.192461099. [28] Pilon-Thomas S, Mackay A, Vohra N, et al. Blockade of programmed death ligand 1 enhances the therapeutic efficacy of combination immunotherapy against melanoma[J]. J Immunol, 2010, 184(7):3442-3449. DOI:10.4049/jimmunol.0904114. [29] Doi T, Piha-Paul SA, Jalal SI, et al. Safety and antitumor activity of the anti-programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma[J]. J Clin Oncol, 2018, 36(1):61-67. DOI:10.1200/JCO.2017.74.9846. [30] Shah MA, Kojima T, Hochhauser D, et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus:the phase 2 KEYNOTE-180study[J]. JAMA Oncol, 2019, 5(4):546-550. DOI:10.1001/jamaoncol.2018.5441. [31] Kojima T, Shah MA, Muro K, et al. Randomized phase Ⅲ keynote-181study of pembrolizumab versus chemotherapy in advanced esophageal cancer[J]. J Clin Oncol, 2020, 38(35):4138-4148. DOI:10.1200/JCO.20.01888. [32] Shah M,Adenis A,Enzinger P,et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer-Phase 3 KEYNOTE-181study[C]. Chicago, USA:American Society of Clinical Oncology (ASCO), 2019. [33] Delaney G, Jacob S, Featherstone C, et al. The role of radiotherapy in cancer treatment:estimating optimal utilization from a review of evidence-based clinical guidelines[J]. Cancer, 2005, 104(6):1129-1137. DOI:10.1002/cncr.21324. [34] Park SS, Dong H, Liu X, et al. PD-1 restrains radiotherapy-induced abscopal effect[J]. Cancer Immunol Res, 2015, 3(6):610-619. DOI:10.1158/2326-6066.CIR-14-0138. [35] Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice[J]. J Clin Invest, 2014, 124(2):687-695. DOI:10.1172/JCI67313. [36] Demaria S, Formenti SC. Radiotherapy effects on anti-tumor immunity:implications for cancer treatment[J]. Front Oncol, 2013, 3:128. DOI:10.3389/fonc.2013.00128. [37] Sato H, NIImi A, Yasuhara T, et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells[J]. Nat Commun, 2017, 8(1):1751. DOI:10.1038/s41467-017-01883-9. [38] Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody mpdl3280A in cancer patients[J]. Nature, 2014, 515(7528):563-567. DOI:10.1038/nature14011. [39] Harris TJ, Hipkiss EL, Borzillary S, et al. Radiotherapy augments the immune response to prostate cancer in a time-dependent manner[J]. Prostate, 2008, 68(12):1319-1329. DOI:10.1002/pros.20794. [40] Tian L, Goldstein A, Wang H, et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming[J]. Nature, 2017, 544(7649):250-254. DOI:10.1038/nature21724. [41] Zheng X, Fang Z, Liu X, et al. Increased vessel perfusion predicts the efficacy of immune checkpoint blockade[J]. J Clin Invest, 2018, 128(5):2104-2115. DOI:10.1172/JCI96582. [42] Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice[J]. J Clin Invest, 2014, 124(2):687-695. DOI:10.1172/JCI67313. [43] Hong M,Kim H,Park S,et al. A phase Ⅱ trial of preoperative chemoradiotherapy and pembrolizumab for locally advanced esophageal squamous cell carcinoma[C]. Chicago, USA:American Society of Clinical Oncology (ASCO), 2019. [44] Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade[J]. Cancer Res, 2014, 74(19):5458-5468. DOI:10.1158/0008-5472.CAN-14-1258. [45] Dovedi SJ, Illidge TM. The antitumor immune response generated by fractionated radiation therapy may be limited by tumor cell adaptive resistance and can be circumvented by PD-L1 blockade[J]. Oncoimmunology, 2015, 4(7):e1016709. DOI:10.1080/2162402X.2015.1016709. [46] Guttmann DM, Mitra N, Bekelman J, et al. Improved overall survival with aggressive primary tumor radiotherapy for patients with metastatic esophageal cancer[J]. J Thorac Oncol, 2017, 12(7):1131-1142. DOI:10.1016/j.jtho.2017.03.026.
2022, Vol. 31 
