Mechanisms of Anti-PD Therapy Resistance in Digestive System Neoplasms

Yuxia      Wu; Xiangyan      Jiang; Zeyuan      Yu; Zongrui      Xing; Yong      Ma; Huiguo      Qing
Abstract

Digestive system neoplasms are highly heterogeneous and exhibit complex resistance mechanisms that render anti-programmed cell death protein (PD) therapies poorly effective. The tumor microenvironment (TME) plays a pivotal role in tumor development, apart from supplying energy for tumor proliferation and impeding the body's anti-tumor immune response, the TME actively facilitates tumor progression and immune escape via diverse pathways, which include the modulation of heritable gene expression alterations and the intricate interplay with the gut microbiota. In this review, we aim to elucidate the mechanisms underlying drug resistance in digestive tumors, focusing on immune-mediated resistance, microbial crosstalk, metabolism, and epigenetics. We will highlight the unique characteristics of each digestive tumor and emphasize the significance of the tumor immune microenvironment (TIME). Furthermore, we will discuss the current therapeutic strategies that hold promise for combination with cancer immune normalization therapies. This review aims to provide a thorough understanding of the resistance mechanisms in digestive tumors and offer insights into potential therapeutic interventions.
Keywords: Immunotherapy resistance, normalization cancer immunotherapy, PD-1/B7-H1, anti-PD-1/PD-L1 therapy, digestive system neoplasms, pancreatic cancer.
[1]
Rebecca L, Siegel MPH, Kimberly D, Miller MPH. Nikita Sandeep Wagle MBBS, M., PhD, Ahmedin Jemal DVM, PhD Cancer statistics, 2022; 2023

[2]
Kalafati L, Kourtzelis I, Schulte-Schrepping J, et al. Innate immune training of granulopoiesis promotes anti-tumor activity. Cell  2020; 183(3): 771-785.e12.
 [http://dx.doi.org/10.1016/j.cell.2020.09.058] [PMID:  33125892]

[3]
Leko V, Rosenberg SA. Identifying and targeting human tumor antigens for t cell-based immunotherapy of solid tumors. Cancer Cell  2020; 38(4): 454-72.
 [http://dx.doi.org/10.1016/j.ccell.2020.07.013] [PMID:  32822573]

[4]
Schürch CM, Bhate SS, Barlow GL, et al. Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front. Cell  2020; 182(5): 1341-1359.e19.
 [http://dx.doi.org/10.1016/j.cell.2020.07.005] [PMID:  32763154]

[5]
El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet  2017; 389(10088): 2492-502.
 [http://dx.doi.org/10.1016/S0140-6736(17)31046-2] [PMID:  28434648]

[6]
Du W, Frankel TL, Green M, Zou W. IFNγ signaling integrity in colorectal cancer immunity and immunotherapy. Cell Mol Immunol  2022; 19(1): 23-32.
 [http://dx.doi.org/10.1038/s41423-021-00735-3] [PMID:  34385592]

[7]
Wang F, Wei XL, Wang FH, et al. Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib/II clinical trial NCT02915432. Ann Oncol  2019; 30(9): 1479-86.
 [http://dx.doi.org/10.1093/annonc/mdz197] [PMID:  31236579]

[8]
Wei XL, Ren C, Wang FH, et al. A phase I study of toripalimab, an anti‐PD‐1 antibody, in patients with refractory malignant solid tumors. Cancer Commun  2020; 40(8): 345-54.
 [http://dx.doi.org/10.1002/cac2.12068] [PMID:  32589350]

[9]
Kim ST, Cristescu R, Bass AJ, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med  2018; 24(9): 1449-58.
 [http://dx.doi.org/10.1038/s41591-018-0101-z] [PMID:  30013197]

[10]
Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase 2 trial. Lancet Oncol  2018; 19(7): 940-52.
 [http://dx.doi.org/10.1016/S1470-2045(18)30351-6] [PMID:  29875066]

[11]
Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science  2011; 331(6024): 1565-70.
 [http://dx.doi.org/10.1126/science.1203486] [PMID:  21436444]

[12]
Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape. Curr Opin Immunol  2014; 27: 16-25.
 [http://dx.doi.org/10.1016/j.coi.2014.01.004] [PMID:  24531241]

[13]
Teng MWL, Galon J, Fridman WH, Smyth MJ. From mice to humans: Developments in cancer immunoediting. J Clin Invest  2015; 125(9): 3338-46.
 [http://dx.doi.org/10.1172/JCI80004] [PMID:  26241053]

[14]
Smyth MJ, Ngiow SF, Ribas A, Teng MWL. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol  2016; 13(3): 143-58.
 [http://dx.doi.org/10.1038/nrclinonc.2015.209] [PMID:  26598942]

[15]
O’Donnell JS, Teng MWL, Smyth MJ. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol  2019; 16(3): 151-67.
 [http://dx.doi.org/10.1038/s41571-018-0142-8] [PMID:  30523282]

[16]
Shergold AL, Millar R, Nibbs RJB. Understanding and overcoming the resistance of cancer to PD-1/PD-L1 blockade. Pharmacol Res  2019; 145: 104258.
 [http://dx.doi.org/10.1016/j.phrs.2019.104258] [PMID:  31063806]

[17]
Jiang Y, Chen M, Nie H, Yuan Y. PD-1 and PD-L1 in cancer immunotherapy: Clinical implications and future considerations. Hum Vaccin Immunother  2019; 15(5): 1111-22.
 [http://dx.doi.org/10.1080/21645515.2019.1571892] [PMID:  30888929]

[18]
Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. Journal of experimental & clinical cancer research. CR (East Lansing Mich)  2019; 38(1): 255.

[19]
Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med  2016; 375(18): 1767-78.
 [http://dx.doi.org/10.1056/NEJMra1514296] [PMID:  27806234]

[20]
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.
 [http://dx.doi.org/10.1126/scitranslmed.aad7118] [PMID:  26936508]

[21]
Poltavets V, Kochetkova M, Pitson SM, Samuel MS. The role of the extracellular matrix and its molecular and cellular regulators in cancer cell plasticity. Front Oncol  2018; 8: 431.
 [http://dx.doi.org/10.3389/fonc.2018.00431] [PMID:  30356678]

[22]
Vesely MD, Zhang T, Chen L. Resistance mechanisms to anti-PD cancer immunotherapy. Annu Rev Immunol  2022; 40(1): 45-74.
 [http://dx.doi.org/10.1146/annurev-immunol-070621-030155] [PMID:  35471840]

[23]
Kim TK, Vandsemb EN, Herbst RS, Chen L. Adaptive immune resistance at the tumour site: Mechanisms and therapeutic opportunities. Nat Rev Drug Discov  2022; 21(7): 529-40.
 [http://dx.doi.org/10.1038/s41573-022-00493-5] [PMID:  35701637]

[24]
Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov  2019; 18(3): 197-218.
 [http://dx.doi.org/10.1038/s41573-018-0007-y] [PMID:  30610226]

[25]
Majidpoor J, Mortezaee K. The efficacy of PD-1/PD-L1 blockade in cold cancers and future perspectives. Clin Immunol  2021; 226: 108707.
 [http://dx.doi.org/10.1016/j.clim.2021.108707] [PMID:  33662590]

[26]
Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med  2018; 24(5): 541-50.
 [http://dx.doi.org/10.1038/s41591-018-0014-x] [PMID:  29686425]

[27]
Spranger S, Gajewski TF. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat Rev Cancer  2018; 18(3): 139-47.
 [http://dx.doi.org/10.1038/nrc.2017.117] [PMID:  29326431]

[28]
Wang Q, Shen X, Chen G, Du J. How to overcome resistance to immune checkpoint inhibitors in colorectal cancer: From mechanisms to translation. Int J Cancer  2023; 153(4): 709-22.
 [http://dx.doi.org/10.1002/ijc.34464] [PMID:  36752642]

[29]
Grasso CS, Giannakis M, Wells DK, et al. Genetic mechanisms of immune evasion in colorectal cancer. Cancer Discov  2018; 8(6): 730-49.
 [http://dx.doi.org/10.1158/2159-8290.CD-17-1327] [PMID:  29510987]

[30]
Ruiz de Galarreta M, Bresnahan E, Molina-Sánchez P, et al. β-Catenin activation promotes immune escape and resistance to Anti–PD-1 therapy in hepatocellular carcinoma. Cancer Discov  2019; 9(8): 1124-41.
 [http://dx.doi.org/10.1158/2159-8290.CD-19-0074] [PMID:  31186238]

[31]
Li J, Lee Y, Li Y, et al. Co-inhibitory Molecule B7 Superfamily Member 1 expressed by tumor-infiltrating myeloid cells induces dysfunction of anti-tumor CD8+ T Cells. Immunity  2018; 48(4): 773-786.e5.
 [http://dx.doi.org/10.1016/j.immuni.2018.03.018] [PMID:  29625896]

[32]
Abril-Rodriguez G, Ribas A. SnapShot: Immune checkpoint inhibitors. Cancer Cell  2017; 31(6): 848-848.e1.
 [http://dx.doi.org/10.1016/j.ccell.2017.05.010] [PMID:  28609660]

[33]
Zhang J, Dang F, Ren J, Wei W. Biochemical aspects of PD-L1 regulation in cancer immunotherapy. Trends Biochem Sci  2018; 43(12): 1014-32.
 [http://dx.doi.org/10.1016/j.tibs.2018.09.004] [PMID:  30287140]

[34]
Zhao T, Li Y, Zhang J, Zhang BPD. L1 expression increased by IFN γ via JAK2 STAT1 signaling and predicts a poor survival in colorectal cancer. Oncol Lett  2020; 20(2): 1127-34.
 [http://dx.doi.org/10.3892/ol.2020.11647] [PMID:  32724352]

[35]
Chen C, Wang Z, Ding Y, Qin Y. Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma. Front Immunol  2023; 14: 1133308.
 [http://dx.doi.org/10.3389/fimmu.2023.1133308] [PMID:  36845131]

[36]
Sundar R, Smyth EC, Peng S, Yeong JPS, Tan P. Predictive biomarkers of immune checkpoint inhibition in gastroesophageal cancers. Front Oncol  2020; 10: 763.
 [http://dx.doi.org/10.3389/fonc.2020.00763] [PMID:  32500029]

[37]
Mandal R, Samstein RM, Lee KW, et al. Genetic diversity of tumors with mismatch repair deficiency influences anti–PD-1 immunotherapy response. Science  2019; 364(6439): 485-91.
 [http://dx.doi.org/10.1126/science.aau0447] [PMID:  31048490]

[38]
Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science  2017; 357(6349): 409-13.
 [http://dx.doi.org/10.1126/science.aan6733] [PMID:  28596308]

[39]
Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science  2015; 348(6230): 69-74.
 [http://dx.doi.org/10.1126/science.aaa4971] [PMID:  25838375]

[40]
Salem ME, Puccini A, Grothey A, et al. Landscape of tumor mutation load, mismatch repair deficiency, and PD-L1 expression in a large patient cohort of gastrointestinal cancers. Mol Cancer Res  2018; 16(5): 805-12.
 [http://dx.doi.org/10.1158/1541-7786.MCR-17-0735] [PMID:  29523759]

[41]
Chan TA, Yarchoan M, Jaffee E, et al. Development of tumor mutation burden as an immunotherapy biomarker: Utility for the oncology clinic. Ann Oncol  2019; 30(1): 44-56.
 [http://dx.doi.org/10.1093/annonc/mdy495] [PMID:  30395155]

[42]
Campbell BB, Light N, Fabrizio D, et al. Comprehensive analysis of hypermutation in human cancer. Cell  2017; 171(5): 1042-1056.e10.
 [http://dx.doi.org/10.1016/j.cell.2017.09.048] [PMID:  29056344]

[43]
Maby P, Tougeron D, Hamieh M, et al. Correlation between Density of CD8+ T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: A rationale for personalized immunotherapy. Cancer Res  2015; 75(17): 3446-55.
 [http://dx.doi.org/10.1158/0008-5472.CAN-14-3051] [PMID:  26060019]

[44]
Qamra A, Xing M, Padmanabhan N, et al. Epigenomic promoter alterations amplify gene isoform and immunogenic diversity in gastric adenocarcinoma. Cancer Discov  2017; 7(6): 630-51.
 [http://dx.doi.org/10.1158/2159-8290.CD-16-1022] [PMID:  28320776]

[45]
Anderson P, Aptsiauri N, Ruiz-Cabello F, Garrido F. HLA class I loss in colorectal cancer: Implications for immune escape and immunotherapy. Cell Mol Immunol  2021; 18(3): 556-65.
 [http://dx.doi.org/10.1038/s41423-021-00634-7] [PMID:  33473191]

[46]
Giannakis M, Mu XJ, Shukla SA, et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep  2016; 17(4): 1206.
 [http://dx.doi.org/10.1016/j.celrep.2016.10.009] [PMID:  27760322]

[47]
Kloor M, Becker C, Benner A, et al. Immunoselective pressure and human leukocyte antigen class I antigen machinery defects in microsatellite unstable colorectal cancers. Cancer Res  2005; 65(14): 6418-24.
 [http://dx.doi.org/10.1158/0008-5472.CAN-05-0044] [PMID:  16024646]

[48]
Dierssen JWF, de Miranda NFCC, Ferrone S, et al. HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression. BMC Cancer  2007; 7(1): 33.
 [http://dx.doi.org/10.1186/1471-2407-7-33] [PMID:  17316446]

[49]
Ijsselsteijn ME, Petitprez F, Lacroix L, et al. Revisiting immune escape in colorectal cancer in the era of immunotherapy. Br J Cancer  2019; 120(8): 815-8.
 [http://dx.doi.org/10.1038/s41416-019-0421-x] [PMID:  30862951]

[50]
Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res  2015; 21(4): 687-92.
 [http://dx.doi.org/10.1158/1078-0432.CCR-14-1860] [PMID:  25501578]

[51]
de Charette M, Marabelle A, Houot R. Turning tumour cells into antigen presenting cells: The next step to improve cancer immunotherapy. Eur J Cancer  2016; 68: 134-47.

[52]
Kawazu M, Ueno T, Saeki K, et al. HLA Class I analysis provides insight into the genetic and epigenetic background of immune evasion in colorectal cancer with high microsatellite instability. Gastroenterology  2022; 162(3): 799-812.
 [http://dx.doi.org/10.1053/j.gastro.2021.10.010] [PMID:  34687740]

[53]
Pang K, Shi Z D, Wei L Y, et al.  Research progress of therapeutic effects and drug resistance of immunotherapy based on PD-1/PDL1 blockade. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy  2023; 66: 100907.

[54]
Lin C, He H, Liu H, et al. Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer. Gut  2019; 68(10): 1764-73.
 [http://dx.doi.org/10.1136/gutjnl-2018-316324] [PMID:  30661053]

[55]
Hussain SM, Kansal RG, Alvarez MA, et al. Role of TGF-β in pancreatic ductal adenocarcinoma progression and PD-L1 expression. Cell Oncol  2021; 44(3): 673-87.
 [http://dx.doi.org/10.1007/s13402-021-00594-0] [PMID:  33694102]

[56]
Tsukamoto M, Imai K, Ishimoto T, et al. PD ‐L1 expression enhancement by infiltrating macrophage‐derived tumor necrosis factor‐α leads to poor pancreatic cancer prognosis. Cancer Sci  2019; 110(1): 310-20.
 [http://dx.doi.org/10.1111/cas.13874] [PMID:  30426611]

[57]
He Q, Liu M, Huang W, et al. IL‐1β‐Induced elevation of solute carrier family 7 member 11 promotes hepatocellular carcinoma metastasis through up‐regulating programmed death ligand 1 and colony‐stimulating factor 1. Hepatology  2021; 74(6): 3174-93.
 [http://dx.doi.org/10.1002/hep.32062] [PMID:  34288020]

[58]
Loeuillard E, Yang J, Buckarma E, et al. Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma. J Clin Invest  2020; 130(10): 5380-96.
 [http://dx.doi.org/10.1172/JCI137110] [PMID:  32663198]

[59]
Ju X, Zhang H, Zhou Z, Chen M, Wang Q. Tumor-associated macrophages induce PD-L1 expression in gastric cancer cells through IL-6 and TNF-ɑ signaling. Exp Cell Res  2020; 396(2): 112315.
 [http://dx.doi.org/10.1016/j.yexcr.2020.112315] [PMID:  33031808]

[60]
Zhang H, Liu L, Liu J, et al. Roles of tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for solid cancers. Mol Cancer  2023; 22(1): 58.
 [http://dx.doi.org/10.1186/s12943-023-01725-x] [PMID:  36941614]

[61]
Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell  2008; 133(5): 775-87.
 [http://dx.doi.org/10.1016/j.cell.2008.05.009] [PMID:  18510923]

[62]
Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: Impact on clinical outcome. Nat Rev Cancer  2012; 12(4): 298-306.
 [http://dx.doi.org/10.1038/nrc3245] [PMID:  22419253]

[63]
Overacre-Delgoffe AE, Chikina M, Dadey RE, et al. Interferon-γ Drives Treg fragility to promote anti-tumor immunity. Cell  2017; 169(6): 1130-1141.e11.
 [http://dx.doi.org/10.1016/j.cell.2017.05.005] [PMID:  28552348]

[64]
Merghoub T, Wolchok JD. Curbing Tregs’ (Lack of). Enthusiasm Cell  2017; 169(6): 981-2.
 [http://dx.doi.org/10.1016/j.cell.2017.05.027] [PMID:  28575677]

[65]
Sieminska I, Baran J. Myeloid-derived suppressor cells in colorectal cancer. Front Immunol  2020; 11: 1526.
 [http://dx.doi.org/10.3389/fimmu.2020.01526] [PMID:  32849517]

[66]
Lu T, Ramakrishnan R, Altiok S, et al. Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest  2011; 121(10): 4015-29.
 [http://dx.doi.org/10.1172/JCI45862] [PMID:  21911941]

[67]
Katoh H, Wang D, Daikoku T, Sun H, Dey SK, DuBois RN. CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis. Cancer Cell  2013; 24(5): 631-44.
 [http://dx.doi.org/10.1016/j.ccr.2013.10.009] [PMID:  24229710]

[68]
Solito S, Falisi E, Diaz-Montero CM, et al. A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood  2011; 118(8): 2254-65.
 [http://dx.doi.org/10.1182/blood-2010-12-325753] [PMID:  21734236]

[69]
Sirica AE. The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma. Nat Rev Gastroenterol Hepatol  2012; 9(1): 44-54.
 [http://dx.doi.org/10.1038/nrgastro.2011.222] [PMID:  22143274]

[70]
Gan LL, Hii LW, Wong SF, Leong CO, Mai CW. Molecular mechanisms and potential therapeutic reversal of pancreatic cancer-induced immune evasion. Cancers  2020; 12(7): 1872.
 [http://dx.doi.org/10.3390/cancers12071872] [PMID:  32664564]

[71]
Valkenburg KC, de Groot AE, Pienta KJ. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol  2018; 15(6): 366-81.
 [http://dx.doi.org/10.1038/s41571-018-0007-1] [PMID:  29651130]

[72]
Gorchs L, Fernández Moro C, Bankhead P, et al. Human pancreatic carcinoma-associated fibroblasts promote expression of co-inhibitory markers on CD4+ and CD8+ T-Cells. Front Immunol  2019; 10: 847.
 [http://dx.doi.org/10.3389/fimmu.2019.00847] [PMID:  31068935]

[73]
Virgin HW, Wherry EJ, Ahmed R. Redefining chronic viral infection. Cell  2009; 138(1): 30-50.
 [http://dx.doi.org/10.1016/j.cell.2009.06.036] [PMID:  19596234]

[74]
Wherry EJ. T cell exhaustion. Nat Immunol  2011; 12(6): 492-9.
 [http://dx.doi.org/10.1038/ni.2035] [PMID:  21739672]

[75]
Chiu DKC, Yuen VWH, Cheu JWS, et al. Hepatocellular carcinoma cells up-regulate PVRL1, Stabilizing PVR and Inhibiting the Cytotoxic T-Cell Response via TIGIT to Mediate Tumor Resistance to PD1 Inhibitors in Mice. Gastroenterology  2020; 159(2): 609-23.
 [http://dx.doi.org/10.1053/j.gastro.2020.03.074] [PMID:  32275969]

[76]
Zhou S, Wang Y, Zhang R, et al. Association of Sialic Acid–Binding Immunoglobulin-Like Lectin 15 With Phenotypes in Esophageal Squamous Cell Carcinoma in the Setting of Neoadjuvant Chemoradiotherapy. JAMA Netw Open  2023; 6(1): e2250965.
 [http://dx.doi.org/10.1001/jamanetworkopen.2022.50965] [PMID:  36648946]

[77]
Li H, Zhu R, Liu X, Zhao K, Hong D. Siglec-15 regulates the inflammatory response and polarization of tumor-associated macrophages in pancreatic cancer by inhibiting the cgas-sting signaling pathway. Oxid Med Cell Longev  2022; 2022: 1-14.
 [http://dx.doi.org/10.1155/2022/3341038] [PMID:  36105484]

[78]
Sun J, Lu Q, Sanmamed MF, Wang J. Siglec-15 as an emerging target for next-generation cancer immunotherapy. Clin Cancer Res  2021; 27(3): 680-8.
 [http://dx.doi.org/10.1158/1078-0432.CCR-19-2925] [PMID:  32958700]

[79]
Escors D, Gato-Cañas M, Zuazo M, et al. The intracellular signalosome of PD-L1 in cancer cells. Signal Transduct Target Ther  2018; 3(1): 26.
 [http://dx.doi.org/10.1038/s41392-018-0022-9] [PMID:  30275987]

[80]
Ahmed A, Tait SWG. Targeting immunogenic cell death in cancer. Mol Oncol  2020; 14(12): 2994-3006.
 [http://dx.doi.org/10.1002/1878-0261.12851] [PMID:  33179413]

[81]
Xia C, Yin S, To KKW, Fu L. CD39/CD73/A2AR pathway and cancer immunotherapy. Mol Cancer  2023; 22(1): 44.
 [http://dx.doi.org/10.1186/s12943-023-01733-x] [PMID:  36859386]

[82]
Zhang PF, Gao C, Huang XY, et al. Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma. Mol Cancer  2020; 19(1): 110.
 [http://dx.doi.org/10.1186/s12943-020-01222-5] [PMID:  32593303]

[83]
Luo C, Xin H, Zhou Z, et al. Tumor‐derived exosomes induce immunosuppressive macrophages to foster intrahepatic cholangiocarcinoma progression. Hepatology  2022; 76(4): 982-99.
 [http://dx.doi.org/10.1002/hep.32387] [PMID:  35106794]

[84]
Iida N, Dzutsev A, Stewart CA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science  2013; 342(6161): 967-70.
 [http://dx.doi.org/10.1126/science.1240527] [PMID:  24264989]

[85]
Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy. Science  2015; 350(6264): 1084-9.
 [http://dx.doi.org/10.1126/science.aac4255] [PMID:  26541606]

[86]
Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science  2015; 350(6264): 1079-84.
 [http://dx.doi.org/10.1126/science.aad1329] [PMID:  26541610]

[87]
Peng Z, Cheng S, Kou Y, et al. The gut microbiome is associated with clinical response to Anti–PD-1/PD-L1 immunotherapy in gastrointestinal cancer. Cancer Immunol Res  2020; 8(10): 1251-61.
 [http://dx.doi.org/10.1158/2326-6066.CIR-19-1014] [PMID:  32855157]

[88]
Zheng Y, Wang T, Tu X, et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunother Cancer  2019; 7(1): 193.
 [http://dx.doi.org/10.1186/s40425-019-0650-9] [PMID:  31337439]

[89]
Mao J, Wang D, Long J, et al. Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers. J Immunother Cancer  2021; 9(12): e003334.
 [http://dx.doi.org/10.1136/jitc-2021-003334] [PMID:  34873013]

[90]
Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol  2018; 29(6): 1437-44.
 [http://dx.doi.org/10.1093/annonc/mdy103] [PMID:  29617710]

[91]
Zhou J, Huang G, Wong WC, et al. The impact of antibiotic use on clinical features and survival outcomes of cancer patients treated with immune checkpoint inhibitors. Front Immunol  2022; 13: 968729.
 [http://dx.doi.org/10.3389/fimmu.2022.968729] [PMID:  35967438]

[92]
Pinato DJ, Gramenitskaya D, Altmann DM, et al. Antibiotic therapy and outcome from immune-checkpoint inhibitors. J Immunother Cancer  2019; 7(1): 287.
 [http://dx.doi.org/10.1186/s40425-019-0775-x] [PMID:  31694714]

[93]
Yin P, Liu X, Mansfield AS, et al. CpG-induced antitumor immunity requires IL-12 in expansion of effector cells and down-regulation of PD-1. Oncotarget  2016; 7(43): 70223-31.
 [http://dx.doi.org/10.18632/oncotarget.11833] [PMID:  27602959]

[94]
Wang S, Campos J, Gallotta M, et al. Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8 + T cells. Proc Natl Acad Sci  2016; 113(46): E7240-9.
 [http://dx.doi.org/10.1073/pnas.1608555113] [PMID:  27799536]

[95]
Peuker K, Strigli A, Tauriello DVF, et al. Microbiota-dependent activation of the myeloid calcineurin-NFAT pathway inhibits B7H3- and B7H4-dependent anti-tumor immunity in colorectal cancer. Immunity  2022; 55(4): 701-717.e7.
 [http://dx.doi.org/10.1016/j.immuni.2022.03.008] [PMID:  35364006]

[96]
Peuker K, Muff S, Wang J, et al. Epithelial calcineurin controls microbiota-dependent intestinal tumor development. Nat Med  2016; 22(5): 506-15.
 [http://dx.doi.org/10.1038/nm.4072] [PMID:  27043494]

[97]
Dong X, Pan P, Zheng DW, Bao P, Zeng X, Zhang XZ. Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to remodel tumor-immune microenvironment against colorectal cancer. Sci Adv  2020; 6(20): 1590.
 [http://dx.doi.org/10.1126/sciadv.aba1590]

[98]
Hezaveh K, Shinde RS, Klötgen A, et al. Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity. Immunity  2022; 55(2): 324-340.e8.
 [http://dx.doi.org/10.1016/j.immuni.2022.01.006] [PMID:  35139353]

[99]
Loo TM, Kamachi F, Watanabe Y, et al. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. Cancer Discov  2017; 7(5): 522-38.
 [http://dx.doi.org/10.1158/2159-8290.CD-16-0932] [PMID:  28202625]

[100]
Bell HN, Huber AK, Singhal R, et al. Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer. Cell Metab  2023; 35(1): 134-149.e6.
 [http://dx.doi.org/10.1016/j.cmet.2022.11.013] [PMID:  36528023]

[101]
Tanoue T, Morita S, Plichta DR, et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature  2019; 565(7741): 600-5.
 [http://dx.doi.org/10.1038/s41586-019-0878-z] [PMID:  30675064]

[102]
Mohseni AH, Taghinezhad-S S, Casolaro V, Lv Z, Li D. Potential links between the microbiota and T cell immunity determine the tumor cell fate. Cell Death Dis  2023; 14(2): 154.
 [http://dx.doi.org/10.1038/s41419-023-05560-2] [PMID:  36828830]

[103]
Fluckiger A, Daillère R, Sassi M, et al. Cross-reactivity between tumor MHC class I–restricted antigens and an enterococcal bacteriophage. Science  2020; 369(6506): 936-42.
 [http://dx.doi.org/10.1126/science.aax0701] [PMID:  32820119]

[104]
Kalaora S, Nagler A, Nejman D, et al. Identification of bacteria-derived HLA-bound peptides in melanoma. Nature  2021; 592(7852): 138-43.
 [http://dx.doi.org/10.1038/s41586-021-03368-8] [PMID:  33731925]

[105]
Bolte LA, Lee KA, Björk JR, et al. Association of a mediterranean diet with outcomes for patients treated with immune checkpoint blockade for advanced melanoma. JAMA Oncol  2023; 9(5): 705-9.
 [http://dx.doi.org/10.1001/jamaoncol.2022.7753] [PMID:  36795408]

[106]
Spencer CN, McQuade JL, Gopalakrishnan V, et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science  2021; 374(6575): 1632-40.
 [http://dx.doi.org/10.1126/science.aaz7015] [PMID:  34941392]

[107]
Westheim AJF, Stoffels LM, Dubois LJ, et al. Fatty acids as a tool to boost cancer immunotherapy efficacy. Front Nutr  2022; 9: 868436.
 [http://dx.doi.org/10.3389/fnut.2022.868436] [PMID:  35811951]

[108]
DePeaux K, Delgoffe GM. Metabolic barriers to cancer immunotherapy. Nat Rev Immunol  2021; 21(12): 785-97.
 [http://dx.doi.org/10.1038/s41577-021-00541-y] [PMID:  33927375]

[109]
Martinez-Outschoorn UE, Peiris-Pagés M, Pestell RG, Sotgia F, Lisanti MP. Cancer metabolism: A therapeutic perspective. Nat Rev Clin Oncol  2017; 14(1): 11-31.
 [http://dx.doi.org/10.1038/nrclinonc.2016.60] [PMID:  27141887]

[110]
Long L, Wei J, Lim SA, et al. CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity. Nature  2021; 600(7888): 308-13.
 [http://dx.doi.org/10.1038/s41586-021-04109-7] [PMID:  34795452]

[111]
Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell  2008; 134(5): 703-7.
 [http://dx.doi.org/10.1016/j.cell.2008.08.021] [PMID:  18775299]

[112]
Chang CH, Qiu J, O’Sullivan D, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell  2015; 162(6): 1229-41.
 [http://dx.doi.org/10.1016/j.cell.2015.08.016] [PMID:  26321679]

[113]
Delgoffe GM, Kole TP, Zheng Y, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity  2009; 30(6): 832-44.
 [http://dx.doi.org/10.1016/j.immuni.2009.04.014] [PMID:  19538929]

[114]
Chen DP, Ning WR, Jiang ZZ, et al. Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma. J Hepatol  2019; 71(2): 333-43.
 [http://dx.doi.org/10.1016/j.jhep.2019.04.007] [PMID:  31071366]

[115]
Vasaikar S, Huang C, Wang X, et al. Proteogenomic analysis of human colon cancer reveals new therapeutic opportunities. Cell  2019; 177(4): 1035-1049.e19.
 [http://dx.doi.org/10.1016/j.cell.2019.03.030] [PMID:  31031003]

[116]
Wilde L, Roche M, Domingo-Vidal M, et al. Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development. Semin Oncol  2017; 44(3): 198-203.
 [http://dx.doi.org/10.1053/j.seminoncol.2017.10.004] [PMID:  29248131]

[117]
Wang ZH, Peng WB, Zhang P, Yang XP, Zhou Q. Lactate in the tumour microenvironment: From immune modulation to therapy. EBioMedicine  2021; 73: 103627.
 [http://dx.doi.org/10.1016/j.ebiom.2021.103627] [PMID:  34656878]

[118]
Hayes C, Donohoe CL, Davern M, Donlon NE. The oncogenic and clinical implications of lactate induced immunosuppression in the tumour microenvironment. Cancer Lett  2021; 500: 75-86.
 [http://dx.doi.org/10.1016/j.canlet.2020.12.021] [PMID:  33347908]

[119]
Lundø K, Trauelsen M, Pedersen SF, Schwartz TW. Why warburg works: Lactate controls immune evasion through GPR81. Cell Metab  2020; 31(4): 666-8.
 [http://dx.doi.org/10.1016/j.cmet.2020.03.001] [PMID:  32268113]

[120]
Kumagai S, Koyama S, Itahashi K, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell  2022; 40(2): 201-218.e9.
 [http://dx.doi.org/10.1016/j.ccell.2022.01.001] [PMID:  35090594]

[121]
Ward PS, Thompson CB. Metabolic reprogramming: A cancer hallmark even warburg did not anticipate. Cancer Cell  2012; 21(3): 297-308.
 [http://dx.doi.org/10.1016/j.ccr.2012.02.014] [PMID:  22439925]

[122]
Masoud R, Reyes-Castellanos G, Lac S, et al. Targeting mitochondrial complex I overcomes chemoresistance in high OXPHOS pancreatic cancer. Cell Rep Med  2020; 1(8): 100143.
 [http://dx.doi.org/10.1016/j.xcrm.2020.100143] [PMID:  33294863]

[123]
Yu W, Lei Q, Yang L, et al. Contradictory roles of lipid metabolism in immune response within the tumor microenvironment. J Hematol Oncol  2021; 14(1): 187.
 [http://dx.doi.org/10.1186/s13045-021-01200-4] [PMID:  34742349]

[124]
Ericksen RE, Lim SL, McDonnell E, et al. Loss of BCAA catabolism during carcinogenesis enhances mTORC1 activity and promotes tumor development and progression. Cell Metab  2019; 29(5): 1151-1165.e6.
 [http://dx.doi.org/10.1016/j.cmet.2018.12.020] [PMID:  30661928]

[125]
Lauria G, Curcio R, Lunetti P, et al. Role of mitochondrial transporters on metabolic rewiring of pancreatic adenocarcinoma: A comprehensive review. Cancers  2023; 15(2): 411.
 [http://dx.doi.org/10.3390/cancers15020411] [PMID:  36672360]

[126]
Najumudeen AK, Ceteci F, Fey SK, et al. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer. Nat Genet  2021; 53(1): 16-26.
 [http://dx.doi.org/10.1038/s41588-020-00753-3] [PMID:  33414552]

[127]
Scalise M, Pochini L, Galluccio M, Console L, Indiveri C. Glutamine transport and mitochondrial metabolism in cancer cell growth. Front Oncol  2017; 7: 306.
 [http://dx.doi.org/10.3389/fonc.2017.00306] [PMID:  29376023]

[128]
Wang D, Wan X. Progress in research on the role of amino acid metabolic reprogramming in tumour therapy: A review. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie  2022; 156: 113923.

[129]
Mullen NJ, Singh PK. Nucleotide metabolism: A pan-cancer metabolic dependency. Nat Rev Cancer  2023; 23(5): 275-94.
 [http://dx.doi.org/10.1038/s41568-023-00557-7] [PMID:  36973407]

[130]
Young A, Mittal D, Stagg J, Smyth MJ. Targeting cancer-derived adenosine: New therapeutic approaches. Cancer Discov  2014; 4(8): 879-88.
 [http://dx.doi.org/10.1158/2159-8290.CD-14-0341] [PMID:  25035124]

[131]
Ohta A, Gorelik E, Prasad SJ, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA  2006; 103(35): 13132-7.
 [http://dx.doi.org/10.1073/pnas.0605251103] [PMID:  16916931]

[132]
Maj T, Wang W, Crespo J, et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol  2017; 18(12): 1332-41.
 [http://dx.doi.org/10.1038/ni.3868] [PMID:  29083399]

[133]
Cai XY, Wang XF, Li J, et al. High expression of CD39 in gastric cancer reduces patient outcome following radical resection. Oncol Lett  2016; 12(5): 4080-6.
 [http://dx.doi.org/10.3892/ol.2016.5189] [PMID:  27895775]

[134]
King RJ, Shukla SK, He C, et al. CD73 induces GM-CSF/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis. Oncogene  2022; 41(7): 971-82.
 [http://dx.doi.org/10.1038/s41388-021-02132-6] [PMID:  35001076]

[135]
Vijayan D, Young A, Teng MWL, Smyth MJ. Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer  2017; 17(12): 709-24.
 [http://dx.doi.org/10.1038/nrc.2017.86] [PMID:  29059149]

[136]
Wang J, Wang Y, Chu Y, et al. Tumor-derived adenosine promotes macrophage proliferation in human hepatocellular carcinoma. J Hepatol  2021; 74(3): 627-37.
 [http://dx.doi.org/10.1016/j.jhep.2020.10.021] [PMID:  33137360]

[137]
Barsoum IB, Smallwood CA, Siemens DR, Graham CH. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res  2014; 74(3): 665-74.
 [http://dx.doi.org/10.1158/0008-5472.CAN-13-0992] [PMID:  24336068]

[138]
Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res  2012; 18(16): 4266-76.
 [http://dx.doi.org/10.1158/1078-0432.CCR-11-3114] [PMID:  22896693]

[139]
Noman MZ, Desantis G, Janji B, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med  2014; 211(5): 781-90.
 [http://dx.doi.org/10.1084/jem.20131916] [PMID:  24778419]

[140]
Kumar V, Gabrilovich DI. Hypoxia‐inducible factors in regulation of immune responses in tumour microenvironment. Immunology  2014; 143(4): 512-9.
 [http://dx.doi.org/10.1111/imm.12380] [PMID:  25196648]

[141]
Doedens AL, Phan AT, Stradner MH, et al. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat Immunol  2013; 14(11): 1173-82.
 [http://dx.doi.org/10.1038/ni.2714] [PMID:  24076634]

[142]
Intlekofer AM, Dematteo RG, Venneti S, et al. Hypoxia induces production of L-2-Hydroxyglutarate. Cell Metab  2015; 22(2): 304-11.
 [http://dx.doi.org/10.1016/j.cmet.2015.06.023] [PMID:  26212717]

[143]
Gupta VK, Sharma NS, Durden B, et al. Hypoxia-driven oncometabolite L-2HG maintains stemness-differentiation balance and facilitates immune evasion in pancreatic cancer. Cancer Res  2021; 81(15): 4001-13.
 [http://dx.doi.org/10.1158/0008-5472.CAN-20-2562] [PMID:  33990397]

[144]
Jung G, Hernández-Illán E, Moreira L, Balaguer F, Goel A. Epigenetics of colorectal cancer: Biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol  2020; 17(2): 111-30.
 [http://dx.doi.org/10.1038/s41575-019-0230-y] [PMID:  31900466]

[145]
Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control. Nat Rev Genet  2016; 17(8): 487-500.
 [http://dx.doi.org/10.1038/nrg.2016.59] [PMID:  27346641]

[146]
Ehrlich M. DNA methylation in cancer: Too much, but also too little. Oncogene  2002; 21(35): 5400-13.
 [http://dx.doi.org/10.1038/sj.onc.1205651] [PMID:  12154403]

[147]
Shi R, Zhao H, Zhao S, Yuan H. Molecular subtypes, prognostic and immunotherapeutic relevant gene signatures mediated by DNA methylation regulators in hepatocellular carcinoma. Aging  2022; 14(12): 5271-91.
 [http://dx.doi.org/10.18632/aging.204155] [PMID:  35771147]

[148]
Sundar R, Huang KK, Qamra A, et al. Epigenomic promoter alterations predict for benefit from immune checkpoint inhibition in metastatic gastric cancer. Ann Oncol  2019; 30(3): 424-30.
 [http://dx.doi.org/10.1093/annonc/mdy550] [PMID:  30624548]

[149]
Sundar R, Huang KK, Kumar V, et al. Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition. Gut  2022; 71(7): 1277-88.
 [http://dx.doi.org/10.1136/gutjnl-2021-324420] [PMID:  34433583]

[150]
Bass AJ, Thorsson V, Shmulevich I, et al. Comprehensive molecular characterization of gastric adenocarcinoma. Nature  2014; 513(7517): 202-9.
 [http://dx.doi.org/10.1038/nature13480] [PMID:  25079317]

[151]
Kataoka K, Shiraishi Y, Takeda Y, et al. Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. Nature  2016; 534(7607): 402-6.
 [http://dx.doi.org/10.1038/nature18294] [PMID:  27281199]

[152]
Fu Y, Dominissini D, Rechavi G, He C. Gene expression regulation mediated through reversible m6A RNA methylation. Nat Rev Genet  2014; 15(5): 293-306.
 [http://dx.doi.org/10.1038/nrg3724] [PMID:  24662220]

[153]
Liu X, Wang C, Liu W, et al. Distinct features of H3K4me3 and H3K27me3 chromatin domains in pre-implantation embryos. Nature  2016; 537(7621): 558-62.
 [http://dx.doi.org/10.1038/nature19362] [PMID:  27626379]

[154]
Lu C, Liu Z, Klement JD, et al. WDR5-H3K4me3 epigenetic axis regulates OPN expression to compensate PD-L1 function to promote pancreatic cancer immune escape. J Immunother Cancer  2021; 9(7): e002624.
 [http://dx.doi.org/10.1136/jitc-2021-002624] [PMID:  34326167]

[155]
Wang Y, Cao K. KDM1A promotes immunosuppression in hepatocellular carcinoma by regulating PD-L1 through demethylating MEF2D. J Immunol Res  2021; 2021: 1-19.
 [http://dx.doi.org/10.1155/2021/9965099] [PMID:  34307695]

[156]
Wang X, Zhao J. Targeted cancer therapy based on acetylation and deacetylation of key proteins involved in double-strand break repair. Cancer Manag Res  2022; 14: 259-71.
 [http://dx.doi.org/10.2147/CMAR.S346052] [PMID:  35115826]

[157]
Sim W, Lim WM, Hii LW, Leong CO, Mai CW. Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases. World J Gastroenterol  2022; 28(18): 1934-45.
 [http://dx.doi.org/10.3748/wjg.v28.i18.1934] [PMID:  35664961]

[158]
Hu G, He N, Cai C, et al.  HDAC3 modulates cancer immunity via increasing PD-L1 expression in pancreatic cancer. Pancreatology : official journal of the International Association of Pancreatology (IAP)  2019; 19(2): 383-9.

[159]
Kita Y, Yonemori K, Osako Y, et al. Noncoding RNA and colorectal cancer: Its epigenetic role. J Hum Genet  2017; 62(1): 41-7.
 [http://dx.doi.org/10.1038/jhg.2016.66] [PMID:  27278790]

[160]
Chen L, Gibbons DL, Goswami S, et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun  2014; 5(1): 5241.
 [http://dx.doi.org/10.1038/ncomms6241] [PMID:  25348003]

[161]
Wang Y, Wang D, Xie G, et al. MicroRNA-152 regulates immune response via targeting B7-H1 in gastric carcinoma. Oncotarget  2017; 8(17): 28125-34.
 [http://dx.doi.org/10.18632/oncotarget.15924] [PMID:  28427226]

[162]
Miliotis C, Slack FJ. miR-105-5p regulates PD-L1 expression and tumor immunogenicity in gastric cancer. Cancer Lett  2021; 518: 115-26.
 [http://dx.doi.org/10.1016/j.canlet.2021.05.037] [PMID:  34098061]

[163]
Guo W, Wang Y, Yang M, et al. LincRNA-immunity landscape analysis identifies EPIC1 as a regulator of tumor immune evasion and immunotherapy resistance. Sci Adv  2021; 7(7): eabb3555.
 [http://dx.doi.org/10.1126/sciadv.abb3555] [PMID:  33568470]

[164]
Chen LL. The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol  2016; 17(4): 205-11.
 [http://dx.doi.org/10.1038/nrm.2015.32] [PMID:  26908011]

[165]
Chen DL, Sheng H, Zhang DS, et al. The circular RNA circDLG1 promotes gastric cancer progression and anti-PD-1 resistance through the regulation of CXCL12 by sponging miR-141-3p. Mol Cancer  2021; 20(1): 166.
 [http://dx.doi.org/10.1186/s12943-021-01475-8] [PMID:  34911533]

[166]
Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: Recognition and management. Blood  2016; 127(26): 3321-30.
 [http://dx.doi.org/10.1182/blood-2016-04-703751] [PMID:  27207799]

[167]
Vinay DS, Ryan EP, Pawelec G, et al. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol  2015; 35 (Suppl.): S185-98.
 [http://dx.doi.org/10.1016/j.semcancer.2015.03.004] [PMID:  25818339]

[168]
Sanmamed MF, Chen L. A paradigm shift in cancer immunotherapy: From enhancement to normalization. Cell  2018; 175(2): 313-26.
 [http://dx.doi.org/10.1016/j.cell.2018.09.035] [PMID:  30290139]

[169]
Burton EM, Tawbi HA. Bispecific antibodies to PD-1 and CTLA4: Doubling down on t cells to decouple efficacy from toxicity. Cancer Discov  2021; 11(5): 1008-10.
 [http://dx.doi.org/10.1158/2159-8290.CD-21-0257] [PMID:  33947716]

[170]
Liu F, Liu Y, Chen Z. Tim-3 expression and its role in hepatocellular carcinoma. J Hematol Oncol  2018; 11(1): 126.
 [http://dx.doi.org/10.1186/s13045-018-0667-4] [PMID:  30309387]

[171]
Wang P, Chen Y, Long Q, et al. Increased coexpression of PD-L1 and TIM3/TIGIT is associated with poor overall survival of patients with esophageal squamous cell carcinoma. J Immunother Cancer  2021; 9(10): e002836.
 [http://dx.doi.org/10.1136/jitc-2021-002836] [PMID:  34625514]

[172]
Zhou G, Sprengers D, Boor PPC, et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating t cells in hepatocellular carcinomas. Gastroenterology  2017; 153(4): 1107-1119.e10.
 [http://dx.doi.org/10.1053/j.gastro.2017.06.017] [PMID:  28648905]

[173]
Freed-Pastor WA, Lambert LJ, Ely ZA, et al. The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer. Cancer Cell  2021; 39(10): 1342-1360.e14.
 [http://dx.doi.org/10.1016/j.ccell.2021.07.007] [PMID:  34358448]

[174]
Peng H, Fu YX. The inhibitory PVRL1/PVR/TIGIT axis in immune therapy for hepatocellular carcinoma. Gastroenterology  2020; 159(2): 434-6.
 [http://dx.doi.org/10.1053/j.gastro.2020.06.024] [PMID:  32574623]

[175]
He W, Zhang H, Han F, et al. CD155T/TIGIT signaling regulates CD8+ T-cell metabolism and promotes tumor progression in human gastric cancer. Cancer Res  2017; 77(22): 6375-88.
 [http://dx.doi.org/10.1158/0008-5472.CAN-17-0381] [PMID:  28883004]

[176]
Ge Z, Zhou G, Campos Carrascosa L, et al. TIGIT and PD1 Co-blockade Restores ex vivo Functions of Human Tumor-Infiltrating CD8+ T Cells in Hepatocellular Carcinoma. Cell Mol Gastroenterol Hepatol  2021; 12(2): 443-64.
 [http://dx.doi.org/10.1016/j.jcmgh.2021.03.003] [PMID:  33781741]

[177]
Yan X, Duan H, Ni Y, et al. Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, single-arm, phase II study (TD-NICE). Int J Surg  2022; 103: 106680.
 [http://dx.doi.org/10.1016/j.ijsu.2022.106680] [PMID:  35595021]

[178]
Li Y, Zhou A, Liu S, et al. Comparing a PD-L1 inhibitor plus chemotherapy to chemotherapy alone in neoadjuvant therapy for locally advanced ESCC: A randomized Phase II clinical trial. BMC Med  2023; 21(1): 86.
 [http://dx.doi.org/10.1186/s12916-023-02804-y] [PMID:  36882775]

[179]
Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet  2021; 398(10294): 27-40.
 [http://dx.doi.org/10.1016/S0140-6736(21)00797-2] [PMID:  34102137]

[180]
Song Y, Zhang B, Xin D, et al. First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial. Nat Med  2023; 29(2): 473-82.
 [http://dx.doi.org/10.1038/s41591-022-02179-2] [PMID:  36732627]

[181]
Yang X, Chen B, Wang Y, et al. Real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma patients. Hepatol Int  2023; 17(3): 709-19.
 [http://dx.doi.org/10.1007/s12072-022-10480-y] [PMID:  36753026]

[182]
Wang XH, Liu CJ, Wen HQ, et al. Effectiveness of lenvatinib plus immune checkpoint inhibitors in primary advanced hepatocellular carcinoma beyond oligometastasis. Clin Transl Med  2023; 13(3): e1214.
 [http://dx.doi.org/10.1002/ctm2.1214] [PMID:  36855781]

[183]
Yarchoan M, Cope L, Ruggieri AN, et al. Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers. J Clin Invest  2021; 131(24): e152670.
 [http://dx.doi.org/10.1172/JCI152670] [PMID:  34907910]

[184]
Li X, Li Y, Dong L, et al. Decitabine priming increases anti–PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models. J Clin Invest  2023; 133(7): e165673.
 [http://dx.doi.org/10.1172/JCI165673] [PMID:  36853831]

[185]
Christmas BJ, Rafie CI, Hopkins AC, et al. Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs. Cancer Immunol Res  2018; 6(12): 1561-77.
 [http://dx.doi.org/10.1158/2326-6066.CIR-18-0070] [PMID:  30341213]

[186]
Wu Y, Sang M, Liu F, et al. Epigenetic modulation combined with PD-1/PD-L1 blockade enhances immunotherapy based on MAGE-A11 antigen-specific CD8+T cells against esophageal carcinoma. Carcinogenesis  2020; 41(7): 894-903.
 [http://dx.doi.org/10.1093/carcin/bgaa057] [PMID:  32529260]

[187]
Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science  2018; 359(6371): 91-7.
 [http://dx.doi.org/10.1126/science.aan3706] [PMID:  29097494]

[188]
Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science  2018; 359(6371): 97-103.
 [http://dx.doi.org/10.1126/science.aan4236] [PMID:  29097493]

[189]
Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients. Science  2018; 359(6371): 104-8.
 [http://dx.doi.org/10.1126/science.aao3290] [PMID:  29302014]

[190]
Mirji G, Worth A, Bhat SA, et al. The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer. Sci Immunol  2022; 7(75): eabn0704.
 [http://dx.doi.org/10.1126/sciimmunol.abn0704] [PMID:  36083892]

[191]
Ogino S, Nowak JA, Hamada T, Milner DA Jr, Nishihara R. Insights into pathogenic interactions among environment, host, and tumor at the crossroads of molecular pathology and epidemiology. Annu Rev Pathol  2019; 14(1): 83-103.
 [http://dx.doi.org/10.1146/annurev-pathmechdis-012418-012818] [PMID:  30125150]

[192]
Inamura K, Hamada T, Bullman S, Ugai T, Yachida S, Ogino S. Cancer as microenvironmental, systemic and environmental diseases: opportunity for transdisciplinary microbiomics science. Gut  2022; 71(10): 2107-22.
 [http://dx.doi.org/10.1136/gutjnl-2022-327209] [PMID:  35820782]

[193]
Hu B, Yu M, Ma X, et al. IFNα potentiates Anti–PD-1 efficacy by remodeling glucose metabolism in the hepatocellular carcinoma microenvironment. Cancer Discov  2022; 12(7): 1718-41.
 [http://dx.doi.org/10.1158/2159-8290.CD-21-1022] [PMID:  35412588]

[194]
Cappellesso F, Orban MP, Shirgaonkar N, et al. Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer. Nat Can  2022; 3(12): 1464-83.
 [http://dx.doi.org/10.1038/s43018-022-00470-2] [PMID:  36522548]

[195]
Qin L, Wang L, Zhang J, et al. Therapeutic strategies targeting uPAR potentiate anti–PD-1 efficacy in diffuse-type gastric cancer. Sci Adv  2022; 8(21): eabn3774.
 [http://dx.doi.org/10.1126/sciadv.abn3774] [PMID:  35613265]

[196]
Akiyama T, Yasuda T, Uchihara T, et al. Stromal reprogramming through dual PDGFRα/β blockade boosts the efficacy of Anti–PD-1 immunotherapy in fibrotic tumors. Cancer Res  2023; 83(5): 753-70.
 [http://dx.doi.org/10.1158/0008-5472.CAN-22-1890] [PMID:  36543251]

[197]
Wang Y, Wei B, Gao J, et al. Combination of fruquintinib and Anti-PD-1 for the treatment of colorectal cancer. J Immun  2020; 205(10): 2905-15.

[198]
Doleschel D, Hoff S, Koletnik S, et al. Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth. J Exp Clin Cancer Res  2021; 40(1): 288.
 [http://dx.doi.org/10.1186/s13046-021-02043-0] [PMID:  34517894]

[199]
Fu Y, Peng Y, Zhao S, et al. Combination foretinib and anti-PD-1 antibody immunotherapy for colorectal carcinoma. Front Cell Dev Biol  2021; 9: 689727.
 [http://dx.doi.org/10.3389/fcell.2021.689727] [PMID:  34307367]

[200]
Lin H, Wu Y, Chen J, Huang S, Wang Y. (−)-4-O-(4-O-β-D-glucopyranosylcaffeoyl) quinic acid inhibits the function of myeloid-derived suppressor cells to enhance the efficacy of anti-pd1 against colon cancer. Pharm Res  2018; 35(9): 183.
 [http://dx.doi.org/10.1007/s11095-018-2459-5] [PMID:  30062658]

[201]
Greco R, Qu H, Qu H, et al. Pan-TGFβ inhibition by SAR439459 relieves immunosuppression and improves antitumor efficacy of PD-1 blockade. OncoImmunology  2020; 9(1): 1811605.
 [http://dx.doi.org/10.1080/2162402X.2020.1811605] [PMID:  33224628]

[202]
You D, Hillerman S, Locke G, et al. Enhanced antitumor immunity by a novel small molecule HPK1 inhibitor. J Immunother Cancer  2021; 9(1): e001402.
 [http://dx.doi.org/10.1136/jitc-2020-001402] [PMID:  33408094]

[203]
Kotsiliti E. Targeting hyperactive tRNA modification improves anti-PD1 efficacy. Nat Rev Gastroenterol Hepatol  2023; 20(1): 3.
 [http://dx.doi.org/10.1038/s41575-022-00715-6] [PMID:  36418437]

[204]
Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One  2019; 14(2): e0212513.
 [http://dx.doi.org/10.1371/journal.pone.0212513] [PMID:  30811474]

[205]
Hu Z, Chen G, Zhao Y, et al. Exosome-derived circCCAR1 promotes CD8 + T-cell dysfunction and anti-PD1 resistance in hepatocellular carcinoma. Mol Cancer  2023; 22(1): 55.
 [http://dx.doi.org/10.1186/s12943-023-01759-1] [PMID:  36932387]

[206]
Wei CY, Zhu MX, Zhang PF, et al. PKCα/ZFP64/CSF1 axis resets the tumor microenvironment and fuels anti-PD1 resistance in hepatocellular carcinoma. J Hepatol  2022; 77(1): 163-76.
 [http://dx.doi.org/10.1016/j.jhep.2022.02.019] [PMID:  35219791]
Cite As
Recent Patents on Anti-Cancer Drug Discovery

Mechanisms of Anti-PD Therapy Resistance in Digestive System Neoplasms

Abstract
