Immunotherapy resistance in esophageal cancer: Possible mechanisms and clinical implications

Pinhao Fang, Jianfeng Zhou, Zhiwen Liang, Yushang Yang, Siyuan Luan, Xin Xiao, Xiaokun Li, Hanlu Zhang, Qixin Shang, Xiaoxi Zeng, Yong Yuan, Pinhao Fang, Jianfeng Zhou, Zhiwen Liang, Yushang Yang, Siyuan Luan, Xin Xiao, Xiaokun Li, Hanlu Zhang, Qixin Shang, Xiaoxi Zeng, Yong Yuan

Abstract

Esophageal cancer (EC) is a common malignant gastrointestinal (GI) cancer in adults. Although surgical technology combined with neoadjuvant chemoradiotherapy has advanced rapidly, patients with EC are often diagnosed at an advanced stage and the five-year survival rate remains unsatisfactory. The poor prognosis and high mortality in patients with EC indicate that effective and validated therapy is of great necessity. Recently, immunotherapy has been successfully used in the clinic as a novel therapy for treating solid tumors, bringing new hope to cancer patients. Several immunotherapies, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy, and tumor vaccines, have achieved significant breakthroughs in EC treatment. However, the overall response rate (ORR) of immunotherapy in patients with EC is lower than 30%, and most patients initially treated with immunotherapy are likely to develop acquired resistance (AR) over time. Immunosuppression greatly weakens the durability and efficiency of immunotherapy. Because of the heterogeneity within the immune microenvironment and the highly disparate oncological characteristics in different EC individuals, the exact mechanism of immunotherapy resistance in EC remains elusive. In this review, we provide an overview of immunotherapy resistance in EC, mainly focusing on current immunotherapies and potential molecular mechanisms underlying immunosuppression and drug resistance in immunotherapy. Additionally, we discuss prospective biomarkers and novel methods for enhancing the effect of immunotherapy to provide a clear insight into EC immunotherapy.

Keywords: acquired resistance; biomarker; esophageal cancer; immunotherapy; intrinsic resistance.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Fang, Zhou, Liang, Yang, Luan, Xiao, Li, Zhang, Shang, Zeng and Yuan.

Figures

Figure 1
Figure 1
Activation of immune-checkpoint effects on immune cells. The CD8+ T cells can be activated by interacting with antigen-presenting cells, following which the CD8+ T cells can acquire the capacity to kill tumor cells. However, tumor cells express immune checkpoint proteins that bind to receptors on the surface of CD8+ T cells to evade immune cells; immune checkpoint inhibitor can block this process, thereby allowing CD8+ T cells to kill tumor cells. TCR, T cell receptor; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1.
Figure 2
Figure 2
The mechanism of immune resistance in EC. IL-6, interleukin-6; IL-17, interleukin-17; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; CTLA-4, cytotoxic T lymphocyte-associated protein 4; CCR4, C–C chemokine receptor type 4; CCL2, C–C motif ligand 2; CCL17, C–C motif ligand 17; CCL20, C–C motif ligand 20; CCL22, C–C motif ligand 22; TGF-β, transforming growth factor-β; TIM-3, T cell immunoglobulin and mucin-domain containing-3; LAG-3, lymphocyte-activation gene 3; IFN-γ, interferon-γ; MHC-I, major histocompatibility complex class I; ALDH-1, aldehyde dehydrogenase 1; SIRPα, signal regulatory protein alpha; JAK1, Janus kinase 1; JAK2, Janus kinase 2; Treg, regulatory T cell; CAF, cancer-associated fibroblast; DC, dendritic cell; NK, natural killer; Th17, T helper 17; MDSC, myeloid-derived suppressor cell.
Figure 3
Figure 3
The “abscopal effect” of radiotherapy. When tumor-cell necrosis is induced by radiotherapy, the antigens with the cells are released into the blood, and they can be recognized by immune cells. These activated immune cells could then eliminate the primary tumor or distant metastases.

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. . Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin (2021) 71(3):209–49. doi: 10.3322/caac.21660
    1. Taziki MH, Rajaee S, Behnampour N, Tadrisee M, Mansourian AR. Esophageal cancer: 5-year survival rate at south-East of Caspian Sea of northern Iran. J Cancer Res Ther (2011) 7(2):135–7. doi: 10.4103/0973-1482.82923
    1. Li X, Chen L, Luan S, Zhou J, Xiao X, Yang Y, et al. . The development and progress of nanomedicine for esophageal cancer diagnosis and treatment. Semin Cancer Biol (2022). doi: 10.1016/j.semcancer.2022.01.007
    1. Baxevanis CN, Perez SA, Papamichail M. Cancer immunotherapy. Crit Rev Clin Lab Sci (2009) 46(4):167–89. doi: 10.1080/10408360902937809
    1. Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet (2021) 398(10304):1002–14. doi: 10.1016/s0140-6736(21)01206-x
    1. Zou LQ, Yang X, Li YD, Zhu ZF. Immune checkpoint inhibitors: A new era for esophageal cancer. Expert Rev Anticancer Ther (2019) 19(8):731–8. doi: 10.1080/14737140.2019.1654379
    1. Kiesgen S, Chicaybam L, Chintala NK, Adusumilli PS. Chimeric antigen receptor (Car) T-cell therapy for thoracic malignancies. J Thorac Oncol (2018) 13(1):16–26. doi: 10.1016/j.jtho.2017.10.001
    1. Rieth J, Subramanian S. Mechanisms of intrinsic tumor resistance to immunotherapy. Int J Mol Sci (2018) 19(5):1340. doi: 10.3390/ijms19051340
    1. Dhupar R, van der Kraak L, Pennathur A, Schuchert MJ, Nason KS, Luketich JD, et al. . Targeting immune checkpoints in esophageal cancer: A high mutational load tumor. Ann Thorac Surg (2017) 103(4):1340–9. doi: 10.1016/j.athoracsur.2016.12.011
    1. Li B, Chan HL, Chen P. Immune checkpoint inhibitors: Basics and challenges. Curr Med Chem (2019) 26(17):3009–25. doi: 10.2174/0929867324666170804143706
    1. Yi M, Jiao D, Xu H, Liu Q, Zhao W, Han X, et al. . Biomarkers for predicting efficacy of pd-1/Pd-L1 inhibitors. Mol Cancer (2018) 17(1):129. doi: 10.1186/s12943-018-0864-3
    1. Zou W, Wolchok JD, Chen L. Pd-L1 (B7-H1) and pd-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med (2016) 8(328):328rv4. doi: 10.1126/scitranslmed.aad7118
    1. Park JJ, Omiya R, Matsumura Y, Sakoda Y, Kuramasu A, Augustine MM, et al. . B7-H1/Cd80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood (2010) 116(8):1291–8. doi: 10.1182/blood-2010-01-265975
    1. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature (2017) 541(7637):321–30. doi: 10.1038/nature21349
    1. Kelly RJ. The emerging role of immunotherapy for esophageal cancer. Curr Opin Gastroenterol (2019) 35(4):337–43. doi: 10.1097/mog.0000000000000542
    1. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. . Safety, activity, and immune correlates of anti-Pd-1 antibody in cancer. N Engl J Med (2012) 366(26):2443–54. doi: 10.1056/NEJMoa1200690
    1. Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, et al. . Randomized phase iii keynote-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncol (2020) 38(35):4138–48. doi: 10.1200/jco.20.01888
    1. Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, et al. . Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (Keynote-590): A randomised, placebo-controlled, phase 3 study. Lancet (2021) 398(10302):759–71. doi: 10.1016/s0140-6736(21)01234-4
    1. Zhao Q, Yu J. Meng X. A Good Start Immunother Esophageal Cancer Cancer Med (2019) 8(10):4519–26. doi: 10.1002/cam4.2336
    1. Zhang B, Qi L, Wang X, Xu J, Liu Y, Mu L, et al. . Phase ii clinical trial using camrelizumab combined with apatinib and chemotherapy as the first-line treatment of advanced esophageal squamous cell carcinoma. Cancer Commun (Lond) (2020) 40(12):711–20. doi: 10.1002/cac2.12119
    1. Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, et al. . Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (Attraction-3): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol (2019) 20(11):1506–17. doi: 10.1016/s1470-2045(19)30626-6
    1. Mo H, Huang J, Xu J, Chen X, Wu D, Qu D, et al. . Safety, anti-tumour activity, and pharmacokinetics of fixed-dose shr-1210, an anti-Pd-1 antibody in advanced solid tumours: A dose-escalation, phase 1 study. Br J Cancer (2018) 119(5):538–45. doi: 10.1038/s41416-018-0100-3
    1. Cai Y, Wang F, Liu Q, Li Z, Li D. Sun z. a novel humanized anti-Pd-1 monoclonal antibody potentiates therapy in oral squamous cell carcinoma. Invest N Drugs (2019) 37(5):799–809. doi: 10.1007/s10637-018-0678-6
    1. Fujiwara Y, Iguchi H, Yamamoto N, Hayama M, Nii M, Ueda S, et al. . Tolerability and efficacy of durvalumab in Japanese patients with advanced solid tumors. Cancer Sci (2019) 110(5):1715–23. doi: 10.1111/cas.14003
    1. Jiao R, Luo H, Xu W, Ge H. Immune checkpoint inhibitors in esophageal squamous cell carcinoma: Progress and opportunities. Onco Targets Ther (2019) 12:6023–32. doi: 10.2147/ott.S214579
    1. Krummel MF, Allison JP. Cd28 and ctla-4 have opposing effects on the response of T cells to stimulation. J Exp Med (1995) 182(2):459–65. doi: 10.1084/jem.182.2.459
    1. Van Coillie S, Wiernicki B, Xu J. Molecular and cellular functions of ctla-4. Adv Exp Med Biol (2020) 1248:7–32. doi: 10.1007/978-981-15-3266-5_2
    1. Zhang XF, Pan K, Weng DS, Chen CL, Wang QJ, Zhao JJ, et al. . Cytotoxic T lymphocyte antigen-4 expression in esophageal carcinoma: Implications for prognosis. Oncotarget (2016) 7(18):26670–9. doi: 10.18632/oncotarget.8476
    1. Ralph C, Elkord E, Burt DJ, O'Dwyer JF, Austin EB, Stern PL, et al. . Modulation of lymphocyte regulation for cancer therapy: A phase ii trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin Cancer Res (2010) 16(5):1662–72. doi: 10.1158/1078-0432.Ccr-09-2870
    1. Yang YH, Liu JW, Lu C, Wei JF. Car-T cell therapy for breast cancer: From basic research to clinical application. Int J Biol Sci (2022) 18(6):2609–26. doi: 10.7150/ijbs.70120
    1. June CH, O'Connor RS, Kawalekar OU, Ghassemi S, Milone MC. Car T cell immunotherapy for human cancer. Science (2018) 359(6382):1361–5. doi: 10.1126/science.aar6711
    1. Pang Y, Hou X, Yang C, Liu Y, Jiang G. Advances on chimeric antigen receptor-modified T-cell therapy for oncotherapy. Mol Cancer (2018) 17(1):91. doi: 10.1186/s12943-018-0840-y
    1. Zheng Y, Si J, Yuan T, Ding S, Tian C. Immune targeted therapy for diffuse Large b cell lymphoma. Blood Sci (2021) 3(4):136–48. doi: 10.1097/bs9.0000000000000095
    1. Gill SI, Frey NV, Hexner E, Metzger S, O'Brien M, Hwang WT, et al. . Anti-Cd19 car T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia. Blood Adv (2022). doi: 10.1182/bloodadvances.2022007317
    1. Miao H, Gale NW, Guo H, Qian J, Petty A, Kaspar J, et al. . Epha2 promotes infiltrative invasion of glioma stem cells in vivo through cross-talk with akt and regulates stem cell properties. Oncogene (2015) 34(5):558–67. doi: 10.1038/onc.2013.590
    1. Miyazaki T, Kato H, Fukuchi M, Nakajima M, Kuwano H. Epha2 overexpression correlates with poor prognosis in esophageal squamous cell carcinoma. Int J Cancer (2003) 103(5):657–63. doi: 10.1002/ijc.10860
    1. Shi H, Yu F, Mao Y, Ju Q, Wu Y, Bai W, et al. . Epha2 chimeric antigen receptor-modified T cells for the immunotherapy of esophageal squamous cell carcinoma. J Thorac Dis (2018) 10(5):2779–88. doi: 10.21037/jtd.2018.04.91
    1. Yu F, Wang X, Shi H, Jiang M, Xu J, Sun M, et al. . Development of chimeric antigen receptor-modified T cells for the treatment of esophageal cancer. Tumori (2021) 107(4):341–52. doi: 10.1177/0300891620960223
    1. Zhang H, Zhao H, He X, Xi F, Liu J. Jak-stat domain enhanced Muc1-Car-T cells induced esophageal cancer elimination. Cancer Manag Res (2020) 12:9813–24. doi: 10.2147/cmar.S264358
    1. Xuan Y, Sheng Y, Zhang D, Zhang K, Zhang Z, Ping Y, et al. . Targeting Cd276 by car-T cells induces regression of esophagus squamous cell carcinoma in xenograft mouse models. Transl Oncol (2021) 14(8):101138. doi: 10.1016/j.tranon.2021.101138
    1. Kagoya Y, Tanaka S, Guo T, Anczurowski M, Wang CH, Saso K, et al. . A novel chimeric antigen receptor containing a jak-stat signaling domain mediates superior antitumor effects. Nat Med (2018) 24(3):352–9. doi: 10.1038/nm.4478
    1. Ku GY. The current status of immunotherapies in esophagogastric cancer. Hematol Oncol Clin North Am (2019) 33(2):323–38. doi: 10.1016/j.hoc.2018.12.007
    1. Chen X, Wang L, Li P, Song M, Qin G, Gao Q, et al. . Dual tgf-β and pd-1 blockade synergistically enhances mage-A3-Specific Cd8(+) T cell response in esophageal squamous cell carcinoma. Int J Cancer (2018) 143(10):2561–74. doi: 10.1002/ijc.31730
    1. Zeng G, Aldridge ME, Wang Y, Pantuck AJ, Wang AY, Liu YX, et al. . Dominant b cell epitope from ny-Eso-1 recognized by sera from a wide spectrum of cancer patients: Implications as a potential biomarker. Int J Cancer (2005) 114(2):268–73. doi: 10.1002/ijc.20716
    1. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. . Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med (2010) 363(5):411–22. doi: 10.1056/NEJMoa1001294
    1. Kageyama S, Wada H, Muro K, Niwa Y, Ueda S, Miyata H, et al. . Dose-dependent effects of ny-Eso-1 protein vaccine complexed with cholesteryl pullulan (Chp-Ny-Eso-1) on immune responses and survival benefits of esophageal cancer patients. J Transl Med (2013) 11:246. doi: 10.1186/1479-5876-11-246
    1. Iinuma H, Fukushima R, Inaba T, Tamura J, Inoue T, Ogawa E, et al. . Phase I clinical study of multiple epitope peptide vaccine combined with chemoradiation therapy in esophageal cancer patients. J Transl Med (2014) 12:84. doi: 10.1186/1479-5876-12-84
    1. Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P, et al. . Checkmate-032 study: Efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol (2018) 36(28):2836–44. doi: 10.1200/jco.2017.76.6212
    1. Zhuo N, Liu C, Zhang Q, Li J, Zhang X, Gong J, et al. . Characteristics and prognosis of acquired resistance to immune checkpoint inhibitors in gastrointestinal cancer. JAMA Netw Open (2022) 5(3):e224637. doi: 10.1001/jamanetworkopen.2022.4637
    1. Zhu M, Bekaii-Saab TS. Acquired immunotherapy resistance in gastrointestinal cancers. JAMA Netw Open (2022) 5(3):e224646. doi: 10.1001/jamanetworkopen.2022.4646
    1. Schoenfeld AJ, Hellmann MD. Acquired resistance to immune checkpoint inhibitors. Cancer Cell (2020) 37(4):443–55. doi: 10.1016/j.ccell.2020.03.017
    1. Gardner A, Ruffell B. Dendritic cells and cancer immunity. Trends Immunol (2016) 37(12):855–65. doi: 10.1016/j.it.2016.09.006
    1. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of pd-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J (1992) 11(11):3887–95. doi: 10.1002/j.1460-2075.1992.tb05481.x
    1. Chen K, Cheng G, Zhang F, Zhang N, Li D, Jin J, et al. . Prognostic significance of programmed death-1 and programmed death-ligand 1 expression in patients with esophageal squamous cell carcinoma. Oncotarget (2016) 7(21):30772–80. doi: 10.18632/oncotarget.8956
    1. Ito S, Okano S, Morita M, Saeki H, Tsutsumi S, Tsukihara H, et al. . Expression of pd-L1 and hla class I in esophageal squamous cell carcinoma: Prognostic factors for patient outcome. Ann Surg Oncol (2016) 23(Suppl 4):508–15. doi: 10.1245/s10434-016-5376-z
    1. Kelly RJ, Zaidi AH, Smith MA, Omstead AN, Kosovec JE, Matsui D, et al. . The dynamic and transient immune microenvironment in locally advanced esophageal adenocarcinoma post chemoradiation. Ann Surg (2018) 268(6):992–9. doi: 10.1097/sla.0000000000002410
    1. Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, et al. . Suppression of exosomal pd-L1 induces systemic anti-tumor immunity and memory. Cell (2019) 177(2):414–27.e13. doi: 10.1016/j.cell.2019.02.016
    1. Kiyozumi Y, Baba Y, Okadome K, Yagi T, Ishimoto T, Iwatsuki M, et al. . Ido1 expression is associated with immune tolerance and poor prognosis in patients with surgically resected esophageal cancer. Ann Surg (2019) 269(6):1101–8. doi: 10.1097/sla.0000000000002754
    1. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, et al. . The Cd47-signal regulatory protein alpha (Sirpa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci USA (2012) 109(17):6662–7. doi: 10.1073/pnas.1121623109
    1. Mawby WJ, Holmes CH, Anstee DJ, Spring FA, Tanner MJ. Isolation and characterization of Cd47 glycoprotein: A multispanning membrane protein which is the same as integrin-associated protein (Iap) and the ovarian tumour marker Oa3. Biochem J (1994) 304(Pt 2):525–30. doi: 10.1042/bj3040525
    1. Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R, et al. . Cd47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell (2009) 138(2):271–85. doi: 10.1016/j.cell.2009.05.046
    1. Hatherley D, Harlos K, Dunlop DC, Stuart DI, Barclay AN. The structure of the macrophage signal regulatory protein alpha (Sirpalpha) inhibitory receptor reveals a binding face reminiscent of that used by T cell receptors. J Biol Chem (2007) 282(19):14567–75. doi: 10.1074/jbc.M611511200
    1. Weiskopf K, Jahchan NS, Schnorr PJ, Cristea S, Ring AM, Maute RL, et al. . Cd47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest (2016) 126(7):2610–20. doi: 10.1172/jci81603
    1. Yan T, Cui H, Zhou Y, Yang B, Kong P, Zhang Y, et al. . Multi-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma. Nat Commun (2019) 10(1):1670. doi: 10.1038/s41467-019-09255-1
    1. Derks S, Nason KS, Liao X, Stachler MD, Liu KX, Liu JB, et al. . Epithelial pd-L2 expression marks barrett's esophagus and esophageal adenocarcinoma. Cancer Immunol Res (2015) 3(10):1123–9. doi: 10.1158/2326-6066.Cir-15-0046
    1. Chen Y, Di C, Zhang X, Wang J, Wang F, Yan JF, et al. . Transforming growth factor β signaling pathway: A promising therapeutic target for cancer. J Cell Physiol (2020) 235(3):1903–14. doi: 10.1002/jcp.29108
    1. Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limón P. The polarization of immune cells in the tumour environment by tgfbeta. Nat Rev Immunol (2010) 10(8):554–67. doi: 10.1038/nri2808
    1. Blum AE, Venkitachalam S, Ravillah D, Chelluboyina AK, Kieber-Emmons AM, Ravi L, et al. . Systems biology analyses show hyperactivation of transforming growth factor-β and jnk signaling pathways in esophageal cancer. Gastroenterology (2019) 156(6):1761–74. doi: 10.1053/j.gastro.2019.01.263
    1. Zhang H, Xie C, Yue J, Jiang Z, Zhou R, Xie R, et al. . Cancer-associated fibroblasts mediated chemoresistance by a Foxo1/Tgfβ1 signaling loop in esophageal squamous cell carcinoma. Mol Carcinog (2017) 56(3):1150–63. doi: 10.1002/mc.22581
    1. Chen J, Gingold JA, Su X. Immunomodulatory tgf-β signaling in hepatocellular carcinoma. Trends Mol Med (2019) 25(11):1010–23. doi: 10.1016/j.molmed.2019.06.007
    1. Malladi S, Macalinao DG, Jin X, He L, Basnet H, Zou Y, et al. . Metastatic latency and immune evasion through autocrine inhibition of wnt. Cell (2016) 165(1):45–60. doi: 10.1016/j.cell.2016.02.025
    1. Brabletz T, Pfeuffer I, Schorr E, Siebelt F, Wirth T, Serfling E. Transforming growth factor beta and cyclosporin a inhibit the inducible activity of the interleukin-2 gene in T cells through a noncanonical octamer-binding site. Mol Cell Biol (1993) 13(2):1155–62. doi: 10.1128/mcb.13.2.1155-1162.1993
    1. Li Y, An J, Huang S, He J, Zhang J. Esophageal cancer-derived microvesicles induce regulatory b cells. Cell Biochem Funct (2015) 33(5):308–13. doi: 10.1002/cbf.3115
    1. Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, et al. . Il-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest (1998) 101(2):311–20. doi: 10.1172/jci1368
    1. Hodge DR, Hurt EM, Farrar WL. The role of il-6 and Stat3 in inflammation and cancer. Eur J Cancer (2005) 41(16):2502–12. doi: 10.1016/j.ejca.2005.08.016
    1. Ebbing EA, van der Zalm AP, Steins A, Creemers A, Hermsen S, Rentenaar R, et al. . Stromal-derived interleukin 6 drives epithelial-to-Mesenchymal transition and therapy resistance in esophageal adenocarcinoma. Proc Natl Acad Sci USA (2019) 116(6):2237–42. doi: 10.1073/pnas.1820459116
    1. Vinocha A, Grover RK, Deepak R. Clinical significance of interleukin-6 in diagnosis of lung, oral, esophageal, and gall bladder carcinomas. J Cancer Res Ther (2018) 14(Supplement):S758–s60. doi: 10.4103/0973-1482.183217
    1. Correction for Ebbing et al. . Stromal-derived interleukin 6 drives epithelial-to-Mesenchymal transition and therapy resistance in esophageal adenocarcinoma. Proc Natl Acad Sci USA (2021) 118(37):e2113728118. doi: 10.1073/pnas.2113728118
    1. Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, et al. . Regulation of the innate and adaptive immune responses by stat-3 signaling in tumor cells. Nat Med (2004) 10(1):48–54. doi: 10.1038/nm976
    1. Higashino N, Koma YI, Hosono M, Takase N, Okamoto M, Kodaira H, et al. . Fibroblast activation protein-positive fibroblasts promote tumor progression through secretion of Ccl2 and interleukin-6 in esophageal squamous cell carcinoma. Lab Invest (2019) 99(6):777–92. doi: 10.1038/s41374-018-0185-6
    1. Wang WL, Chang WL, Yang HB, Chang IW, Lee CT, Chang CY, et al. . Quantification of tumor infiltrating Foxp3+ regulatory T cells enables the identification of high-risk patients for developing synchronous cancers over upper aerodigestive tract. Oral Oncol (2015) 51(7):698–703. doi: 10.1016/j.oraloncology.2015.04.015
    1. Sawant DV, Yano H, Chikina M, Zhang Q, Liao M, Liu C, et al. . Adaptive plasticity of il-10(+) and il-35(+) T(Reg) cells cooperatively promotes tumor T cell exhaustion. Nat Immunol (2019) 20(6):724–35. doi: 10.1038/s41590-019-0346-9
    1. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol (2010) 11(1):7–13. doi: 10.1038/ni.1818
    1. Watanabe MA, Oda JM, Amarante MK, Cesar Voltarelli J. Regulatory T cells and breast cancer: Implications for immunopathogenesis. Cancer Metastasis Rev (2010) 29(4):569–79. doi: 10.1007/s10555-010-9247-y
    1. GS. Innate T. Innate and adaptive immune cells in Tumor microenvironment. Gulf J Oncolog (2021) 1(35):77–81.
    1. Nabeki B, Ishigami S, Uchikado Y, Sasaki K, Kita Y, Okumura H, et al. . Interleukin-32 expression and treg infiltration in esophageal squamous cell carcinoma. Anticancer Res (2015) 35(5):2941–7.
    1. Sugiyama D, Nishikawa H, Maeda Y, Nishioka M, Tanemura A, Katayama I, et al. . Anti-Ccr4 mab selectively depletes effector-type Foxp3+Cd4+ regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci USA (2013) 110(44):17945–50. doi: 10.1073/pnas.1316796110
    1. Fourcade J, Sun Z, Kudela P, Janjic B, Kirkwood JM, El-Hafnawy T, et al. . Human tumor antigen-specific helper and regulatory T cells share common epitope specificity but exhibit distinct T cell repertoire. J Immunol (2010) 184(12):6709–18. doi: 10.4049/jimmunol.0903612
    1. Liu JY, Li F, Wang LP, Chen XF, Wang D, Cao L, et al. . Ctl- vs treg lymphocyte-attracting chemokines, Ccl4 and Ccl20, are strong reciprocal predictive markers for survival of patients with oesophageal squamous cell carcinoma. Br J Cancer (2015) 113(5):747–55. doi: 10.1038/bjc.2015.290
    1. Chen D, Hu Q, Mao C, Jiao Z, Wang S, Yu L, et al. . Increased il-17-Producing Cd4(+) T cells in patients with esophageal cancer. Cell Immunol (2012) 272(2):166–74. doi: 10.1016/j.cellimm.2011.10.015
    1. Zhao J, Zhang Z, Luan Y, Zou Z, Sun Y, Li Y, et al. . Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis b virus infection by promoting T helper 17 cell recruitment. Hepatology (2014) 59(4):1331–42. doi: 10.1002/hep.26916
    1. Lu L, Pan K, Zheng HX, Li JJ, Qiu HJ, Zhao JJ, et al. . Il-17a promotes immune cell recruitment in human esophageal cancers and the infiltrating dendritic cells represent a positive prognostic marker for patient survival. J Immunother (2013) 36(8):451–8. doi: 10.1097/CJI.0b013e3182a802cf
    1. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol (2007) 8(4):345–50. doi: 10.1038/ni0407-345
    1. Liu D, Zhang R, Wu J, Pu Y, Yin X, Cheng Y, et al. . Interleukin-17a promotes esophageal adenocarcinoma cell invasiveness through ros-dependent, nf-κb-Mediated mmp-2/9 activation. Oncol Rep (2017) 37(3):1779–85. doi: 10.3892/or.2017.5426
    1. Quezada SA, Peggs KS, Curran MA, Allison JP. Ctla4 blockade and gm-csf combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest (2006) 116(7):1935–45. doi: 10.1172/jci27745
    1. Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, et al. . Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci USA (2008) 105(8):3005–10. doi: 10.1073/pnas.0712237105
    1. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer (2004) 4(1):71–8. doi: 10.1038/nrc1256
    1. Mills CD, Kincaid K, Alt JM, Heilman MJ. Hill AM. m-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol (2000) 164(12):6166–73. doi: 10.4049/jimmunol.164.12.6166
    1. Li J, Xie Y, Wang X, Li F, Li S, Li M, et al. . Prognostic impact of tumor-associated macrophage infiltration in esophageal cancer: A meta-analysis. Future Oncol (2019) 15(19):2303–17. doi: 10.2217/fon-2018-0669
    1. Bingle L, Lewis CE, Corke KP, Reed MW, Brown NJ. Macrophages promote angiogenesis in human breast tumour spheroids in vivo. Br J Cancer (2006) 94(1):101–7. doi: 10.1038/sj.bjc.6602901
    1. Hefetz-Sela S, Stein I, Klieger Y, Porat R, Sade-Feldman M, Zreik F, et al. . Acquisition of an immunosuppressive protumorigenic macrophage phenotype depending on c-jun phosphorylation. Proc Natl Acad Sci USA (2014) 111(49):17582–7. doi: 10.1073/pnas.1409700111
    1. Huang H, Zhang G, Li G, Ma H, Zhang X. Circulating Cd14(+)Hla-Dr(-/Low) myeloid-derived suppressor cell is an indicator of poor prognosis in patients with escc. Tumour Biol (2015) 36(10):7987–96. doi: 10.1007/s13277-015-3426-y
    1. Strober S. Natural suppressor (Ns) cells, neonatal tolerance, and total lymphoid irradiation: Exploring obscure relationships. Annu Rev Immunol (1984) 2:219–37. doi: 10.1146/annurev.iy.02.040184.001251
    1. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol (2009) 9(3):162–74. doi: 10.1038/nri2506
    1. Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J, et al. . Gr-1+Cd115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res (2006) 66(2):1123–31. doi: 10.1158/0008-5472.Can-05-1299
    1. Sinha P, Clements VK, Ostrand-Rosenberg S. Interleukin-13-Regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis. Cancer Res (2005) 65(24):11743–51. doi: 10.1158/0008-5472.Can-05-0045
    1. Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol (2007) 179(2):977–83. doi: 10.4049/jimmunol.179.2.977
    1. Chen MF, Kuan FC, Yen TC, Lu MS, Lin PY, Chung YH, et al. . Il-6-Stimulated Cd11b+ Cd14+ hla-dr- myeloid-derived suppressor cells, are associated with progression and poor prognosis in squamous cell carcinoma of the esophagus. Oncotarget (2014) 5(18):8716–28. doi: 10.18632/oncotarget.2368
    1. Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W, et al. . Fap promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment Via Stat3-Ccl2 signaling. Cancer Res (2016) 76(14):4124–35. doi: 10.1158/0008-5472.Can-15-2973
    1. Karakasheva TA, Waldron TJ, Eruslanov E, Kim SB, Lee JS, O'Brien S, et al. . Cd38-expressing myeloid-derived suppressor cells promote tumor growth in a murine model of esophageal cancer. Cancer Res (2015) 75(19):4074–85. doi: 10.1158/0008-5472.Can-14-3639
    1. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science (2015) 348(6230):69–74. doi: 10.1126/science.aaa4971
    1. Watts C, Powis S. Pathways of antigen processing and presentation. Rev Immunogenet (1999) 1(1):60–74.
    1. Hulpke S, Tampé R. The mhc I loading complex: A multitasking machinery in adaptive immunity. Trends Biochem Sci (2013) 38(8):412–20. doi: 10.1016/j.tibs.2013.06.003
    1. Restifo NP, Marincola FM, Kawakami Y, Taubenberger J, Yannelli JR, Rosenberg SA. Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J Natl Cancer Inst (1996) 88(2):100–8. doi: 10.1093/jnci/88.2.100
    1. Gettinger S, Choi J, Hastings K, Truini A, Datar I, Sowell R, et al. . Impaired hla class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov (2017) 7(12):1420–35. doi: 10.1158/-17-0593
    1. Sade-Feldman M, Jiao YJ, Chen JH, Rooney MS, Barzily-Rokni M, Eliane JP, et al. . Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun (2017) 8(1):1136. doi: 10.1038/s41467-017-01062-w
    1. Wang J, Yang W, Wang T, Chen X, Wang J, Zhang X, et al. . Mesenchymal stromal cells-derived β2-microglobulin promotes epithelial-mesenchymal transition of esophageal squamous cell carcinoma cells. Sci Rep (2018) 8(1):5422. doi: 10.1038/s41598-018-23651-5
    1. Sucker A, Zhao F, Pieper N, Heeke C, Maltaner R, Stadtler N, et al. . Acquired ifnγ resistance impairs anti-tumor immunity and gives rise to T-Cell-Resistant melanoma lesions. Nat Commun (2017) 8:15440. doi: 10.1038/ncomms15440
    1. Gao J, Shi LZ, Zhao H, Chen J, Xiong L, He Q, et al. . Loss of ifn-Γ pathway genes in tumor cells as a mechanism of resistance to anti-Ctla-4 therapy. Cell (2016) 167(2):397–404.e9. doi: 10.1016/j.cell.2016.08.069
    1. Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, et al. . Mutations associated with acquired resistance to pd-1 blockade in melanoma. N Engl J Med (2016) 375(9):819–29. doi: 10.1056/NEJMoa1604958
    1. Li J, Qiu G, Fang B, Dai X, Cai J. Deficiency of il-18 aggravates esophageal carcinoma through inhibiting ifn-Γ production by Cd8(+)T cells and nk cells. Inflammation (2018) 41(2):667–76. doi: 10.1007/s10753-017-0721-3
    1. Zhang C, Jiang F, Su C, Xie P, Xu L. Upregulation of long noncoding rna Snhg20 promotes cell growth and metastasis in esophageal squamous cell carcimona via modulating ATM-JAK-PD-L1 pathway. J. Cell. Biochem. (2019) 120(7):11642–50. doi: 10.1002/jcb.28444
    1. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. . Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science (2016) 351(6280):1463–9. doi: 10.1126/science.aaf1490
    1. Rosenthal R, Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, et al. . Neoantigen-directed immune escape in lung cancer evolution. Nature (2019) 567(7749):479–85. doi: 10.1038/s41586-019-1032-7
    1. Zheng Y, Chen Z, Han Y, Han L, Zou X, Zhou B, et al. . Immune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment. Nat Commun (2020) 11(1):6268. doi: 10.1038/s41467-020-20019-0
    1. Ott PA, Bang YJ, Piha-Paul SA, Razak ARA, Bennouna J, Soria JC, et al. . T-Cell-Inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: Keynote-028. J Clin Oncol (2019) 37(4):318–27. doi: 10.1200/jco.2018.78.2276
    1. Hatogai K, Kitano S, Fujii S, Kojima T, Daiko H, Nomura S, et al. . Comprehensive immunohistochemical analysis of tumor microenvironment immune status in esophageal squamous cell carcinoma. Oncotarget (2016) 7(30):47252–64. doi: 10.18632/oncotarget.10055
    1. Shah MA, Kojima T, Hochhauser D, Enzinger P, Raimbourg J, Hollebecque A, 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-180 study. JAMA Oncol (2019) 5(4):546–50. doi: 10.1001/jamaoncol.2018.5441
    1. Huang J, Xu B, Mo H, Zhang W, Chen X, Wu D, et al. . Safety, activity, and biomarkers of shr-1210, an anti-Pd-1 antibody, for patients with advanced esophageal carcinoma. Clin Cancer Res (2018) 24(6):1296–304. doi: 10.1158/1078-0432.Ccr-17-2439
    1. Hynes CF, Kwon DH, Vadlamudi C, Lofthus A, Iwamoto A, Chahine JJ, et al. . Programmed death ligand 1: A step toward immunoscore for esophageal cancer. Ann Thorac Surg (2018) 106(4):1002–7. doi: 10.1016/j.athoracsur.2018.05.002
    1. Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, et al. . Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res (2005) 11(8):2947–53. doi: 10.1158/1078-0432.Ccr-04-1469
    1. Rosenberg AJ, Wainwright DA, Rademaker A, Galvez C, Genet M, Zhai L, et al. . Indoleamine 2,3-dioxygenase 1 and overall survival of patients diagnosed with esophageal cancer. Oncotarget (2018) 9(34):23482–93. doi: 10.18632/oncotarget.25235
    1. Yang WF, Yu JM, Zuo WS, Wang SZ. [Expression of Cd80, Cd86, tgf-Beta1 and il-10 mrna in the esophageal carcinoma]. Zhonghua Zhong Liu Za Zhi (2006) 28(10):762–5.
    1. Milano F, Jorritsma T, Rygiel AM, Bergman JJ, Sondermeijer C, Ten Brinke A, et al. . Expression pattern of immune suppressive cytokines and growth factors in oesophageal adenocarcinoma reveal a tumour immune escape-promoting microenvironment. Scand J Immunol (2008) 68(6):616–23. doi: 10.1111/j.1365-3083.2008.02183.x
    1. Ammannagari N, Atasoy A. Current status of immunotherapy and immune biomarkers in gastro-esophageal cancers. J Gastrointest Oncol (2018) 9(1):196–207. doi: 10.21037/jgo.2017.06.12
    1. Galon J, Pagès F, Marincola FM, Angell HK, Thurin M, Lugli A, et al. . Cancer classification using the immunoscore: A worldwide task force. J Transl Med (2012) 10:205. doi: 10.1186/1479-5876-10-205
    1. Sharabi A, Kim SS, Kato S, Sanders PD, Patel SP, Sanghvi P, et al. . Exceptional response to nivolumab and stereotactic body radiation therapy (Sbrt) in neuroendocrine cervical carcinoma with high tumor mutational burden: Management considerations from the center for personalized cancer therapy at uc San Diego moores cancer center. Oncologist (2017) 22(6):631–7. doi: 10.1634/theoncologist.2016-0517
    1. Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, et al. . Development of tumor mutation burden as an immunotherapy biomarker: Utility for the oncology clinic. Ann Oncol (2019) 30(1):44–56. doi: 10.1093/annonc/mdy495
    1. Hellmann MD, Callahan MK, Awad MM, Calvo E, Ascierto PA, Atmaca A, et al. . Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell (2018) 33(5):853–61.e4. doi: 10.1016/j.ccell.2018.04.001
    1. Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al. . First-line nivolumab in stage iv or recurrent non-Small-Cell lung cancer. N Engl J Med (2017) 376(25):2415–26. doi: 10.1056/NEJMoa1613493
    1. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. . Genetic basis for clinical response to ctla-4 blockade in melanoma. N Engl J Med (2014) 371(23):2189–99. doi: 10.1056/NEJMoa1406498
    1. Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al. . Liquid biopsies come of age: Towards implementation of circulating tumour DNA. Nat Rev Cancer (2017) 17(4):223–38. doi: 10.1038/nrc.2017.7
    1. Lam VK, Zhang J. Blood-based tumor mutation burden: Continued progress toward personalizing immunotherapy in non-small cell lung cancer. J Thorac Dis (2019) 11(6):2208–11. doi: 10.21037/jtd.2019.05.68
    1. Badmos KB, Adebayo LA, Osinowo AO, Lawal AO, Habeebu MY, Rotimi O, et al. . Mismatch repair protein expressions in cohort of colorectal carcinoma patients in Lagos. Niger J Clin Pract (2021) 24(9):1294–9. doi: 10.4103/njcp.njcp_104_21
    1. De' Angelis GL, Bottarelli L, Azzoni C, De' Angelis N, Leandro G, Di Mario F, et al. . Microsatellite instability in colorectal cancer. Acta BioMed (2018) 89(9-s):97–101. doi: 10.23750/abm.v89i9-S.7960
    1. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. . Pd-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med (2015) 372(26):2509–20. doi: 10.1056/NEJMoa1500596
    1. Matsumoto Y, Nagasaka T, Kambara T, Hoshizima N, Murakami J, Sasamoto H, et al. . Microsatellite instability and clinicopathological features in esophageal squamous cell cancer. Oncol Rep (2007) 18(5):1123–7
    1. Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandalà M, Ryu MH, et al. . Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase iii trial in patients with gastroesophageal adenocarcinoma. Ann Oncol (2021) 32(9):1127–36. doi: 10.1016/j.annonc.2021.05.803
    1. Ajani JA, D'Amico TA, Bentrem DJ, Chao J, Corvera C, Das P, et al. . Esophageal and esophagogastric junction cancers, version 2.2019, nccn clinical practice guidelines in oncology. J Natl Compr Canc Netw (2019) 17(7):855–83. doi: 10.6004/jnccn.2019.0033
    1. Sui H, Ma N, Wang Y, Li H, Liu X, Su Y, et al. . Anti-Pd-1/Pd-L1 therapy for non-Small-Cell lung cancer: Toward personalized medicine and combination strategies. J Immunol Res (2018) 2018:6984948. doi: 10.1155/2018/6984948
    1. Gingrich AA, Kirane AR. Novel targets in melanoma: Intralesional and combination therapy to manipulate the immune response. Surg Oncol Clin N Am (2020) 29(3):467–83. doi: 10.1016/j.soc.2020.02.012
    1. Kato K, Shah MA, Enzinger P, Bennouna J, Shen L, Adenis A, et al. . Keynote-590: Phase iii study of first-line chemotherapy with or without pembrolizumab for advanced esophageal cancer. Future Oncol (2019) 15(10):1057–66. doi: 10.2217/fon-2018-0609
    1. Van Der Kraak L, Goel G, Ramanan K, Kaltenmeier C, Zhang L, Normolle DP, et al. . 5-fluorouracil upregulates cell surface B7-H1 (Pd-L1) expression in gastrointestinal cancers. J Immunother Cancer (2016) 4:65. doi: 10.1186/s40425-016-0163-8
    1. Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, et al. . Ionizing radiation inhibition of distant untreated tumors (Abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys (2004) 58(3):862–70. doi: 10.1016/j.ijrobp.2003.09.012
    1. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, et al. . Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med (2012) 366(10):925–31. doi: 10.1056/NEJMoa1112824
    1. Park SS, Dong H, Liu X, Harrington SM, Krco CJ, Grams MP, et al. . Pd-1 restrains radiotherapy-induced abscopal effect. Cancer Immunol Res (2015) 3(6):610–9. doi: 10.1158/2326-6066.Cir-14-0138
    1. Herrera FG, Bourhis J, Coukos G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin (2017) 67(1):65–85. doi: 10.3322/caac.21358

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit