The role of PD-1/PD-L1 signaling pathway in cancer pathogenesis and treatment: a systematic review

Abstract

Aim: Cancer as a complex disease poses significant challenges for both diagnosis and treatment. Researchers have been exploring various avenues to find effective therapeutic strategies, with a particular emphasis on cellular signaling pathways and immunotherapy. One such pathway that has recently been suggested is the PD-1/PD-L1 pathway, which is an immune checkpoint signaling system that plays an important role in regulating the immune system and maintaining tissue homeostasis. Cancer cells exploit this pathway by producing PD-L1, which attaches to PD-1 on T cells, thus inhibiting immune responses and enabling the cancer cells to escape detection by the immune system. This study aimed to evaluate the role of the PD-1/PD-L1 pathway in cancer pathogenesis and treatment. Method: This study was performed based on the principles of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). All in vitro, in vivo, and clinical studies that were published in English have been considered during a thorough search of the Scopus, Web of Science, and PubMed databases without date restriction until March 2024. Results: According to the studies reviewed, the PD-1/PD-L1 signaling axis suggests promising therapeutic effects on various types of cancers such as non-small cell lung cancer, melanoma, breast cancer, hepatocellular carcinoma, squamous cell carcinoma, and colorectal cancer, among others. Additionally, research suggests that immune checkpoint inhibitors that block PD1/PD-L1, such as pembrolizumab, atezolizumab, nivolumab, durvalumab, cemiplimab, avelumab, etc., can effectively prevent tumor cells from escaping the immune system. Moreover, there might be a possible interaction between microbiome, obesity, etc. on immune mechanisms and on the immune checkpoint inhibitors (ICIs). Conclusion: Although we have gained considerable knowledge about ICIs, we are still facing challenges in effectively prescribing the appropriate ICIs for individual patients. This is largely due to the complex interactions between different intracellular pathways, which need to be thoroughly studied. To resolve this issue, it is necessary to conduct more reliable clinical trials that can produce a scientific consensus.

Keywords

PD-1/PD-L1 pathway / cancer / immunotherapy / immune checkpoint inhibitors

References

[1] Smyth EC,Grabsch HI,Lordick F.Gastric cancer.Lancet2020;396:635-48

[2] Loibl S,Morrow M,Curigliano G.Breast cancer.Lancet2021;397:1750-69

[3] Kelley KD.Cancer.Med Clin North Am2022;106:411-22

[4] de la Peña-López R, Remolina-Bonilla YA. [Cancer].Gac Med Mex2016;152 Suppl 1:63-6

[5] Kroemer G.Tumor cell metabolism: cancer’s Achilles’ heel.Cancer Cell2008;13:472-82

[6] Sharma P,Mathur P.Innovation in cancer therapeutics and regulatory perspectives.Med Oncol2022;39:76 PMCID:PMC8863908

[7] Ai L,Xu J.Roles of PD-1/PD-L1 pathway: signaling, cancer, and beyond.Adv Exp Med Biol2020;1248:33-59

[8] Chen G,Zhang W.Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response.Nature2018;560:382-6

[9] Gordon SR,Dulken BW.PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity.Nature2017;545:495-9 PMCID:PMC5931375

[10] Kim MJ,Park HJ.Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells.Nat Immunol2023;24:148-61

[11] Wartewig T,Schulz M.PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma.Nat Cancer2023;4:1508-25 PMCID:PMC10597841

[12] Topalian SL,Pardoll DM.Neoadjuvant checkpoint blockade for cancer immunotherapy.Science2020;367:eaax0182 PMCID:PMC7789854

[13] Doroshow DB,Beasley MB.PD-L1 as a biomarker of response to immune-checkpoint inhibitors.Nat Rev Clin Oncol2021;18:345-62

[14] Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer2012;12:252-64 PMCID:PMC4856023

[15] Topalian SL,Pardoll DM.Immune checkpoint blockade: a common denominator approach to cancer therapy.Cancer Cell2015;27:450-61 PMCID:PMC4400238

[16] Ferlay J,Dikshit R.Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int J Cancer2015;136:E359-86

[17] Marin-Acevedo JA,Soyano AE,Chumsri S.Next generation of immune checkpoint therapy in cancer: new developments and challenges.J Hematol Oncol2018;11:39 PMCID:PMC5856308

[18] Leemans CR,Brakenhoff RH.The molecular landscape of head and neck cancer.Nat Rev Cancer2018;18:269-82

[19] Siegel RL,Fuchs HE.Cancer statistics, 2021.CA Cancer J Clin2021;71:7-33

[20] Ishida Y,Shibahara K.Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death.EMBO J1992;11:3887-95 PMCID:PMC556898

[21] Dong H,Tamada K.B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion.Nat Med1999;5:1365-9

[22] Freeman GJ,Iwai Y.Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.J Exp Med2000;192:1027-34 PMCID:PMC2193311

[23] Bretscher PA.A two-step, two-signal model for the primary activation of precursor helper T cells.Proc Natl Acad Sci USA1999;96:185-90 PMCID:PMC15114

[24] Oyer JL,Altomare DA.PD-L1 blockade enhances anti-tumor efficacy of NK cells.Oncoimmunology2018;7:e1509819 PMCID:PMC6205063

[25] Ghosh C,Sun Y.A snapshot of the PD-1/PD-L1 pathway.J Cancer2021;12:2735-46 PMCID:PMC8040720

[26] Yi M,Xu L,Wu K.Regulation of PD-L1 expression in the tumor microenvironment.J Hematol Oncol2021;14:10 PMCID:PMC7792099

[27] Fanoni D,Recalcati S.New monoclonal antibodies against B-cell antigens: possible new strategies for diagnosis of primary cutaneous B-cell lymphomas.Immunol Lett2011;134:157-60

[28] Terme M,Aymeric L.IL-18 induces PD-1-dependent immunosuppression in cancer.Cancer Res2011;71:5393-9

[29] Bally AP,Boss JM.Genetic and epigenetic regulation of PD-1 expression.J Immunol2016;196:2431-7 PMCID:PMC4780223

[30] Zhang X,Guo X.Structural and functional analysis of the costimulatory receptor programmed death-1.Immunity2004;20:337-47

[31] Lázár-Molnár E,Cao E,Nathenson SG.Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2.Proc Natl Acad Sci USA2008;105:10483-8 PMCID:PMC2492495

[32] Wolchok JD,Callahan MK.Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med2013;369:122-33

[33] Nishimura H,Hiai H,Honjo T.Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor.Immunity1999;11:141-51

[34] Lake RA.Immunotherapy and chemotherapy-a practical partnership.Nat Rev Cancer2005;5:397-405

[35] Rabinovich GA,Sotomayor EM.Immunosuppressive strategies that are mediated by tumor cells.Annu Rev Immunol2007;25:267-96 PMCID:PMC2895922

[36] Chen L.Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity.Nat Rev Immunol2004;4:336-47

[37] Zou W.Inhibitory B7-family molecules in the tumour microenvironment.Nat Rev Immunol2008;8:467-77

[38] Sznol M.Blockade of the B7-H1/PD-1 pathway as a basis for combination anticancer therapy.Cancer J2014;20:290-5

[39] Taube JM,Young GD.Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape.Sci Transl Med2012;4:127ra37 PMCID:PMC3568523

[40] Jiang X,Giobbie-Hurder A,Hodi FS.The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition.Clin Cancer Res2013;19:598-609

[41] Mittendorf EA,Meric-Bernstam F.PD-L1 expression in triple-negative breast cancer.Cancer Immunol Res2014;2:361-70 PMCID:PMC4000553

[42] Song M,Lu B.PTEN loss increases PD-L1 protein expression and affects the correlation between PD-L1 expression and clinical parameters in colorectal cancer.PLoS One2013;8:e65821 PMCID:PMC3681867

[43] Amani H,Nasseri Maleki S.Targeting signal transducers and activators of transcription (STAT) in human cancer by dietary polyphenolic antioxidants.Biochimie2017;142:63-79

[44] Podojil JR,Miller SD.Therapeutic blockade of T-cell antigen receptor signal transduction and costimulation in autoimmune disease.Adv Exp Med Biol2008;640:234-51 PMCID:PMC2853772

[45] Appleman LJ.T cell anergy and costimulation.Immunol Rev2003;192:161-80

[46] Spranger S,Zha Y.Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8⁺ T cells.Sci Transl Med2013;5:200ra116 PMCID:PMC4136707

[47] Massi D,Merelli B.PD-L1 marks a subset of melanomas with a shorter overall survival and distinct genetic and morphological characteristics.Ann Oncol2014;25:2433-42

[48] Abiko K,Hamanishi J.PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction.Clin Cancer Res2013;19:1363-74

[49] Wang L,Chen X,Xie K.Immune sculpting of norepinephrine on MHC-I, B7-1, IDO and B7-H1 expression and regulation of proliferation and invasion in pancreatic carcinoma cells.PLoS One2012;7:e45491 PMCID:PMC3446877

[50] Kim DH,Choi YJ.Exosomal PD-L1 promotes tumor growth through immune escape in non-small cell lung cancer.Exp Mol Med2019;51:1-13 PMCID:PMC6802663

[51] Al Bakir M,Martínez-Ruiz C.The evolution of non-small cell lung cancer metastases in TRACERx.Nature2023;616:534-42

[52] Mignon S,Van den Eynden G.The relationship between tumor-infiltrating lymphocytes, PD-L1 expression, driver mutations and clinical outcome parameters in non-small cell lung cancer adenocarcinoma in patients with a limited to no smoking history.Pathol Oncol Res2020;26:1221-8

[53] Zhang N,Du W.The EGFR pathway is involved in the regulation of PD-L1 expression via the IL-6/JAK/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer.Int J Oncol2016;49:1360-8

[54] Althammer S,Spitzmüller A.Automated image analysis of NSCLC biopsies to predict response to anti-PD-L1 therapy.J Immunother Cancer2019;7:121 PMCID:PMC6501300

[55] Zhang Y,Gong D,Shen Q.Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8⁺ T lymphocytes in human non-small cell lung cancer.Cell Mol Immunol2010;7:389-95 PMCID:PMC4002677

[56] Akbay EA,Carretero J.Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.Cancer Discov2013;3:1355-63

[57] Huang Z,Lu T.First-line immune-checkpoint inhibitors in non-small cell lung cancer: current landscape and future progress.Front Pharmacol2020;11:578091 PMCID:PMC7577011

[58] Villaruz LC.The clinical utility of PD-L1 testing in selecting non-small cell lung cancer patients for PD1/PD-L1-directed therapy.Clin Pharmacol Ther2016;100:212-4 PMCID:PMC4982801

[59] Sepesi B,Mitchell KG.Prognostic value of PD-L1 mRNA sequencing expression profile in non-small cell lung cancer.Ann Thorac Surg2018;105:1621-6

[60] Tseng JS,Wu CY.Characteristics and predictive value of PD-L1 status in real-world non-small cell lung cancer patients.J Immunother2018;41:292-9

[61] Bozinovski S,Rangamuwa K.Integrating endobronchial ultrasound bronchoscopy with molecular testing of immunotherapy biomarkers in non-small cell lung cancer.Transl Lung Cancer Res2021;10:2779-87 PMCID:PMC8264344

[62] Zhang J,Li Y.Circulating PD-L1 in NSCLC patients and the correlation between the level of PD-L1 expression and the clinical characteristics.Thorac Cancer2015;6:534-8 PMCID:PMC4511334

[63] Zhao S,Li W.Antibiotics are associated with attenuated efficacy of anti-PD-1/PD-L1 therapies in Chinese patients with advanced non-small cell lung cancer.Lung Cancer2019;130:10-7

[64] Cho BC,Hussein M.Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study.Lancet Oncol2022;23:781-92

[65] Herbst RS,Santana-Davila R.Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial.Lancet Oncol2019;20:1109-23

[66] Wrangle JM,Patel MR.ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial.Lancet Oncol2018;19:694-704 PMCID:PMC6089612

[67] Yang R,Huang R.Platycodon grandiflorum Triggers antitumor immunity by restricting PD-1 expression of CD8⁺ T cells in local tumor microenvironment.Front Pharmacol2022;13:774440 PMCID:PMC9046572

[68] Anagnostou VK.Cancer immunotherapy: a future paradigm shift in the treatment of non-small cell lung cancer.Clin Cancer Res2015;21:976-84

[69] Aiad M,Fresco K.Does the combined use of aspirin and immunotherapy result in better outcomes in non-small cell lung cancer than immunotherapy alone?.Cureus2022;14:e25891 PMCID:PMC9190187

[70] Cabrita R,Sanna A.The role of PTEN loss in immune escape, melanoma prognosis and therapy response.Cancers2020;12:742 PMCID:PMC7140048

[71] Tsao H,Wu H,Haluska FG.Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma.J Invest Dermatol2004;122:337-41 PMCID:PMC2586668

[72] Adeleke S,Augustine A.Melanoma-the therapeutic considerations in the clinical practice.Ann Palliat Med2023;12:1355-72

[73] Davis EJ,Sosman JA.Melanoma: what do all the mutations mean?.Cancer2018;124:3490-9 PMCID:PMC6191351

[74] Pietra G,Moretta L.How melanoma cells inactivate NK cells.Oncoimmunology2012;1:974-5 PMCID:PMC3489764

[75] Lee H,Palendira U,Long GV.Targeting NK cells to enhance melanoma response to immunotherapies.Cancers2021;13:1363 PMCID:PMC8002669

[76] Balsamo M,Pietra G.Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity.Proc Natl Acad Sci USA2009;106:20847-52 PMCID:PMC2791633

[77] Alavi S,Kefford RF,Shklovskaya E.Interferon signaling is frequently downregulated in melanoma.Front Immunol2018;9:1414 PMCID:PMC6021492

[78] Taube JM,McMiller TL.Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade.Clin Cancer Res2015;21:3969-76 PMCID:PMC4558237

[79] de Waal AC, Aben KK, van Rossum MM, Kiemeney LA. Melanoma of unknown primary origin: a population-based study in the Netherlands.Eur J Cancer2013;49:676-83

[80] Mehdi A,Mahmood N.Enhanced anticancer effect of a combination of S-adenosylmethionine (SAM) and immune checkpoint inhibitor (ICPi) in a syngeneic mouse model of advanced melanoma.Front Oncol2020;10:1361 PMCID:PMC7492272

[81] Ascierto PA,Anderson AC.Future perspectives in melanoma research: meeting report from the “Melanoma Bridge”, Napoli, December 5th-8th 2013.J Transl Med2014;12:277 PMCID:PMC4232645

[82] Chapman PB,Robert C.Improved survival with vemurafenib in melanoma with BRAF V600E mutation.N Engl J Med2011;364:2507-16 PMCID:PMC3549296

[83] Algazi A,Agarwala S.Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients.Ann Oncol2020;31:532-40

[84] Mahnke K.TIGIT-CD155 interactions in melanoma: a novel Co-inhibitory pathway with potential for clinical intervention.J Invest Dermatol2016;136:9-11

[85] Hu Z,Du G.PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice.PLoS One2020;15:e0228339 PMCID:PMC7098565

[86] Zhang R,Liu X.Microfluidic PLGA microcapsules with PD-L1 aptamers and docetaxel encapsulation for enhancing tumor immunity.Appl Mater Today2022;27:101484

[87] Qiu N,Liu Q.Celastrol nanoemulsion induces immunogenicity and downregulates PD-L1 to boost abscopal effect in melanoma therapy.Biomaterials2021;269:120604 PMCID:PMC8601126

[88] Gu Z,Shi Y.Nanotechnology-mediated immunochemotherapy combined with docetaxel and PD-L1 antibody increase therapeutic effects and decrease systemic toxicity.J Control Release2018;286:369-80

[89] Vera-Aguilera J,Beltran D.Novel treatment of melanoma: combined parasite-derived peptide GK-1 and anti-programmed death ligand 1 therapy.Cancer Biother Radiopharm2017;32:49-56

[90] Rodríguez-Rodríguez N,Bugarin-Estrada E.The helminth-derived peptide GK-1 induces an anti-tumoral CD8 T cell response associated with downregulation of the PD-1/PD-L1 pathway.Clin Immunol2020;212:108240

[91] Liu H,Morse J.T cell mediated immunity after combination therapy with intralesional PV-10 and blockade of the PD-1/PD-L1 pathway in a murine melanoma model.PLoS One2018;13:e0196033 PMCID:PMC5918896

[92] Shi Y,He C.Design of an injectable polypeptide hydrogel depot containing the immune checkpoint blocker anti-PD-L1 and doxorubicin to enhance antitumor combination therapy.Macromol Biosci2021;21:e2100049

[93] Zhao J,Lu Q.Inhibition of post-surgery tumour recurrence via a sprayable chemo-immunotherapy gel releasing PD-L1 antibody and platelet-derived small EVs.J Nanobiotechnol2022;20:62 PMCID:PMC8812025

[94] Wang X,Guo J.Treatment algorithm of metastatic mucosal melanoma.Chin Clin Oncol2014;3:38

[95] Vogt PK.Fortuitous convergences: the beginnings of JUN.Nat Rev Cancer2002;2:465-9

[96] Yu P,Li K.The traditional chinese medicine monomer Ailanthone improves the therapeutic efficacy of anti-PD-L1 in melanoma cells by targeting c-Jun.J Exp Clin Cancer Res2022;41:346 PMCID:PMC9753288

[97] Yazdani M,Alani B.Liposomal gp100 vaccine combined with CpG ODN sensitizes established B16F10 melanoma tumors to anti PD-1 therapy.Iran J Basic Med Sci2020;23:1065-77

[98] Chowdhury PS,Honjo T.Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy.J Intern Med2018;283:110-20

[99] Tian H,Wang Q.A novel cancer vaccine with the ability to simultaneously produce anti-PD-1 antibody and GM-CSF in cancer cells and enhance Th1-biased antitumor immunity.Signal Transduct Target Ther2016;1:16025 PMCID:PMC5661645

[100] Cheng B,Niu X.Discovery of novel resorcinol dibenzyl ethers targeting the programmed cell death-1/programmed cell death-ligand 1 interaction as potential anticancer agents.J Med Chem2020;63:8338-58

[101] Frydenlund N,Yang S.Tumoral PD-L1 expression in desmoplastic melanoma is associated with depth of invasion, tumor-infiltrating CD8 cytotoxic lymphocytes and the mixed cytomorphological variant.Mod Pathol2017;30:357-69

[102] Brahmer JR,Wollner I.Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.J Clin Oncol2010;28:3167-75 PMCID:PMC4834717

[103] Azadnajafabad S,Mohammadi E.Burden of breast cancer and attributable risk factors in the North Africa and Middle East region, 1990-2019: a systematic analysis for the global burden of disease study 2019.Front Oncol2023;13:1132816 PMCID:PMC10431599

[104] Hanamura T,Kagamu H.Immunological profiles of the breast cancer microenvironment represented by tumor-infiltrating lymphocytes and PD-L1 expression.Sci Rep2022;12:8098 PMCID:PMC9110375

[105] Shi F,Zhou Q,Wu GJ.Distribution of CD4⁺ and CD8⁺ exhausted tumor-infiltrating lymphocytes in molecular subtypes of Chinese breast cancer patients.Onco Targets Ther2018;11:6139-45 PMCID:PMC6160273

[106] Zhang J,Luo Y.Association between activation of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway and pain in patients with cancer.Med Sci Monit2019;25:1275-82 PMCID:PMC6387472

[107] Juliá EP,Pampena MB,Levy EM.Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against triple negative breast cancer cells.Front Immunol2018;9:2140 PMCID:PMC6159755

[108] Lamberti G,Andrini E.The mechanisms of PD-L1 regulation in non-small-cell lung cancer (NSCLC): which are the involved players?.Cancers2020;12:3129 PMCID:PMC7692442

[109] Florent L,Slimano F.BRAF V600-mutated metastatic melanoma and targeted therapy resistance: an update of the current knowledge.Cancers2023;15:2607 PMCID:PMC10177463

[110] Ofori S.Small-molecule poly(ADP-ribose) polymerase and PD-L1 inhibitor conjugates as dual-action anticancer agents.ACS Omega2019;4:12584-97 PMCID:PMC6682113

[111] Tie Y,Zhao R.Safety and efficacy of atezolizumab in the treatment of cancers: a systematic review and pooled-analysis.Drug Des Devel Ther2019;13:523-38 PMCID:PMC6366347

[112] Krämer S,Saylan D.Treatment progress in triple negative breast cancer.Eur J Gynaecol Oncol2022;43:341-52

[113] Luo X,Ji D.Carbon nanotubes (CNT)-loaded ginsenosides Rb3 suppresses the PD-1/PD-L1 pathway in triple-negative breast cancer.Aging2021;13:17177-89 PMCID:PMC8312428

[114] Zhao W,Li W.M2-like TAMs function reversal contributes to breast cancer eradication by combination dual immune checkpoint blockade and photothermal therapy.Small2021;17:e2007051

[115] Zhang R,Lv H.Immune checkpoint blockade mediated by a small-molecule nanoinhibitor targeting the PD-1/PD-L1 pathway synergizes with photodynamic therapy to elicit antitumor immunity and antimetastatic effects on breast cancer.Small2019;15:e1903881

[116] Mirzaei-Parsa MJ,Haeri A.Preparation, characterization, and evaluation of the anticancer activity of artemether-loaded nano-niosomes against breast cancer.Breast Cancer2020;27:243-51

[117] Chen Z,Feng L.Senescent cells re-engineered to express soluble programmed death receptor-1 for inhibiting programmed death receptor-1/programmed death ligand-1 as a vaccination approach against breast cancer.Cancer Sci2018;109:1753-63 PMCID:PMC5989746

[118] Ge Y,Ju S.Blockade of PD-1/PD-L1 immune checkpoint during DC vaccination induces potent protective immunity against breast cancer in hu-SCID mice.Cancer Lett2013;336:253-9

[119] Chen LM,Al Haq AT.Oligo-fucoidan supplementation enhances the effect of olaparib on preventing metastasis and recurrence of triple-negative breast cancer in mice.J Biomed Sci2022;29:70 PMCID:PMC9479298

[120] Salatino M,Rabinovich GA.Glycans pave the way for immunotherapy in triple-negative breast cancer.Cancer Cell2018;33:155-7

[121] Liang M.Triptolide inhibits interferon-gamma-induced programmed death-1-ligand 1 surface expression in breast cancer cells.Cancer Lett2008;270:337-41

[122] Zhou Y,Takeshita F,Xiao Z.Delivery of miR-424-5p via extracellular vesicles promotes the apoptosis of MDA-MB-231 TNBC cells in the tumor microenvironment.Int J Mol Sci2021;22:844 PMCID:PMC7831022

[123] Fertal SA,Ponik SM.Stromal characteristics and impact on new therapies for metastatic triple-negative breast cancer.Cancers2022;14:1238 PMCID:PMC8909697

[124] Konstantinopoulos PA,Vidal GA.Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma.JAMA Oncol2019;5:1141-9 PMCID:PMC6567832

[125] Antony GR,Parambil ST.Immunohistochemical expression of PD-L1 and MDR1 in breast tumors: association with clinico-pathological parameters and treatment outcome.Clin Exp Med2023;23:859-69

[126] Afkhami M,Yost SE.Mutation and immune profiling of metaplastic breast cancer: correlation with survival.PLoS One2019;14:e0224726 PMCID:PMC6834262

[127] AiErken N,Zhou Y.High PD-L1 expression is closely associated with tumor-infiltrating lymphocytes and leads to good clinical outcomes in Chinese triple negative breast cancer patients.Int J Biol Sci2017;13:1172-9 PMCID:PMC5666332

[128] Ali HR,Blows FM.PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes.Ann Oncol2015;26:1488-93

[129] Andrieu GP,Smith CL.BET protein targeting suppresses the PD-1/PD-L1 pathway in triple-negative breast cancer and elicits anti-tumor immune response.Cancer Lett2019;465:45-58 PMCID:PMC6901183

[130] Alkaabi D,Sulaiman S,Attoub S.PD-1 independent role of PD-L1 in triple-negative breast cancer progression.Int J Mol Sci2023;24:6420 PMCID:PMC10094894

[131] Llovet JM,Villanueva A.Hepatocellular carcinoma.Nat Rev Dis Primers2021;7:6

[132] Chen Z,Peng L,Tang N.2,5-dimethylcelecoxib improves immune microenvironment of hepatocellular carcinoma by promoting ubiquitination of HBx-induced PD-L1.J Immunother Cancer2020;8:e001377 PMCID:PMC7542662

[133] Peña-Asensio J,Torralba M,Sanz-de-Villalobos E.Anti-PD-1/PD-L1 based combination immunotherapy to boost antigen-specific CD8⁺ T cell response in hepatocellular carcinoma.Cancers2021;13:1922 PMCID:PMC8073815

[134] Pan Z,Shi B.Increased antitumor activities of glypican-3-specific chimeric antigen receptor-modified T cells by coexpression of a soluble PD1-CH3 fusion protein.Cancer Immunol Immunother2018;67:1621-34 PMCID:PMC11028056

[135] Sawada Y,Shimomura M,Endo I.Programmed death-1 blockade enhances the antitumor effects of peptide vaccine-induced peptide-specific cytotoxic T lymphocytes.Int J Oncol2015;46:28-36 PMCID:PMC4238729

[136] Shi F,Zeng Z.PD-1 and PD-L1 upregulation promotes CD8⁺ T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients.Int J Cancer2011;128:887-96

[137] Zeng Z,Zhou L.Upregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation prognosis in patients with HBV-related hepatocellular carcinoma.PLoS One2011;6:e23621 PMCID:PMC3164659

[138] An J,Yu E,Shim JH.The effects of immune checkpoint modulators on the clinical course of patients with resectable hepatocellular carcinoma.J Liver Cancer2022;22:40-50 PMCID:PMC10035709

[139] Wu M,Hu J,Li S.WSX1 act as a tumor suppressor in hepatocellular carcinoma by downregulating neoplastic PD-L1 expression.Nat Commun2021;12:3500 PMCID:PMC8190270

[140] Ajami M,Habibey R,Soleimani M.Effect of DHA+EPA on oxidative stress and apoptosis induced by ischemia-reperfusion in rat kidneys.Fundam Clin Pharmacol2013;27:593-602

[141] Ajami M,Razaz JM.Expression of Bcl-2 and Bax after hippocampal ischemia in DHA + EPA treated rats.Neurol Sci2011;32:811-8

[142] Zarch AV,Soleimani M,Katebi M.Neuroprotective effects of diazoxide and its antagonism by glibenclamide in pyramidal neurons of rat hippocampus subjected to ischemia-reperfusion-induced injury.Int J Neurosci2009;119:1346-61

[143] Yang H,Sun L.Correlation between PD-L2 expression and clinical outcome in solid cancer patients: a meta-analysis.Front Oncol2019;9:47 PMCID:PMC6413700

[144] Ahmed Z,Victor DW.Evidence to date: clinical utility of tremelimumab in the treatment of unresectable hepatocellular carcinoma.J Hepatocell Carcinoma2023;10:1911-22 PMCID:PMC10617526

[145] Tattersall A,Wiggans AJ,Morrison J.Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer.Cochrane Database Syst Rev2022;2:CD007929 PMCID:PMC8848772

[146] Hao L,Peng Q.Dihydroartemisinin reduced lipid droplet deposition by YAP1 to promote the anti-PD-1 effect in hepatocellular carcinoma.Phytomedicine2022;96:153913

[147] Lv T,Yan W,Xu H.Targeting of GSDMD sensitizes HCC to anti-PD-1 by activating cGAS pathway and downregulating PD-L1 expression.J Immunother Cancer2022;10:e004763 PMCID:PMC9189836

[148] Toroudi HP,Bakhtiarian A.Potassium channel modulators and indomethacin-induced gastric ulceration in rats.Scand J Gastroenterol1999;34:962-6

[149] Rahgozar M,Bakhtiarian A.Diazoxide, a K(ATP) opener, accelerates restitution of ethanol or indomethacin-induced gastric ulceration in rats independent of polyamines.J Gastroenterol Hepatol2001;16:290-6

[150] O'Shea JJ,Villarino AV,McInnes IB.The JAK-STAT pathway: impact on human disease and therapeutic intervention.Annu Rev Med2015;66:311-28 PMCID:PMC5634336

[151] Tümen D,Gülow K.Pathogenesis and current treatment strategies of hepatocellular carcinoma.Biomedicines2022;10:3202 PMCID:PMC9775527

[152] Hammarén HM,Raivola J.The regulation of JAKs in cytokine signaling and its breakdown in disease.Cytokine2019;118:48-63

[153] Guangshun S,Xin C.Meloxicam inhibits hepatocellular carcinoma progression and enhances the sensitivity of immunotherapy via the MicroRNA-200/PD-L1 pathway.J Oncol2022;2022:4598573 PMCID:PMC8885196

[154] Starley BQ,Harrison SA.Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection.Hepatology2010;51:1820-32

[155] Xing R,Cui Q.Strategies to improve the antitumor effect of immunotherapy for hepatocellular carcinoma.Front Immunol2021;12:783236 PMCID:PMC8660685

[156] Giglia JL,Berk LB,Dessureault S.Systemic therapy for advanced hepatocellular carcinoma: past, present, and future.Cancer Control2010;17:120-9

[157] Combalia A.Squamous cell carcinoma: an update on diagnosis and treatment.Dermatol Pract Concept2020;10:e2020066 PMCID:PMC7319751

[158] Kujan O,Smaga M.PD-1/PD-L1, Treg-related proteins, and tumour-infiltrating lymphocytes are associated with the development of oral squamous cell carcinoma.Pathology2022;54:409-16

[159] Takada K,Toyokawa G.The expression of PD-L1 protein as a prognostic factor in lung squamous cell carcinoma.Lung Cancer2017;104:7-15

[160] Liu Z,Stewart J,Fuller C.Evaluation of programmed death ligand 1 expression in cytology to determine eligibility for immune checkpoint inhibitor therapy in patients with head and neck squamous cell carcinoma.Cancer Cytopathol2022;130:110-9 PMCID:PMC8810615

[161] Okada S,Ishihara S.Significance of PD-L1 expression in pulmonary metastases from head and neck squamous cell carcinoma.Surg Oncol2018;27:259-65

[162] Troeltzsch M,Pianka A.Is there evidence for the presence and relevance of the PD-1/PD-L1 pathway in oral squamous cell carcinoma? Hints from an immunohistochemical study.J Oral Maxillofac Surg2017;75:969-77

[163] Monteiro de Oliveira Novaes JA,Guijarro I.Targeting of CD40 and PD-L1 pathways inhibits progression of oral premalignant lesions in a carcinogen-induced model of oral squamous cell carcinoma.Cancer Prev Res2021;14:313-24

[164] Akisada N,Takao S.PD-L1 expression in tongue squamous cell carcinoma.Med Mol Morphol2021;54:52-9

[165] Okadome K,Nomoto D.Prognostic and clinical impact of PD-L2 and PD-L1 expression in a cohort of 437 oesophageal cancers.Br J Cancer2020;122:1535-43 PMCID:PMC7217865

[166] Guo W,Li N.Prognostic value of PD-L1 in esophageal squamous cell carcinoma: a meta-analysis.Oncotarget2018;9:13920-33 PMCID:PMC5862626

[167] Cocks M,Jenson EG.Immune checkpoint status and tumor microenvironment in vulvar squamous cell carcinoma.Virchows Arch2020;477:93-102

[168] Curley J,Chinn Z,Stoler M.Looking past PD-L1: expression of immune checkpoint TIM-3 and its ligand galectin-9 in cervical and vulvar squamous neoplasia.Mod Pathol2020;33:1182-92

[169] Heeren AM,Bleeker MC.Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix.Mod Pathol2016;29:753-63 PMCID:PMC4931542

[170] Yang W,Yang YZ,Jin YD.Expressions of programmed death (PD)-1 and PD-1 ligand (PD-L1) in cervical intraepithelial neoplasia and cervical squamous cell carcinomas are of prognostic value and associated with human papillomavirus status.J Obstet Gynaecol Res2017;43:1602-12

[171] Reddy OL,Moatamed NA.Programmed death-ligand 1 (PD-L1) is expressed in a significant number of the uterine cervical carcinomas.Diagn Pathol2017;12:45 PMCID:PMC5473984

[172] Liang Y,Zhou C.Variation of PD-L1 expression in locally advanced cervical cancer following neoadjuvant chemotherapy.Diagn Pathol2020;15:67 PMCID:PMC7271386

[173] Müller T,Dietrich D.PD-L1: a novel prognostic biomarker in head and neck squamous cell carcinoma.Oncotarget2017;8:52889-900 PMCID:PMC5581079

[174] Qiao XW,Pang X.The evolving landscape of PD-1/PD-L1 pathway in head and neck cancer.Front Immunol2020;11:1721 PMCID:PMC7531035

[175] Affolter A,Tengler L.Modulation of PD-L1 expression by standard therapy in head and neck cancer cell lines and exosomes.Int J Oncol2023;63:102 PMCID:PMC10552694

[176] Zhang Z,Peng G.Neoadjuvant chemoimmunotherapy for the treatment of locally advanced head and neck squamous cell carcinoma: a single-arm phase 2 clinical trial.Clin Cancer Res2022;28:3268-76 PMCID:PMC9662919

[177] Wu D,Xu P.Neoadjuvant chemo-immunotherapy with camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck: a pilot phase II trial.Nat Commun2024;15:2177 PMCID:PMC10928200

[178] Huang X,Zhong G.Neoadjuvant toripalimab combined with gemcitabine and cisplatin in resectable locally advanced head and neck squamous cell carcinoma (NeoTGP01): an open label, single-arm, phase Ib clinical trial.J Exp Clin Cancer Res2022;41:300 PMCID:PMC9558942

[179] Li X,Du W,Dai L.Induction chemotherapy combined with immunotherapy in locally advanced head and neck squamous cell carcinoma.BMC Cancer2021;21:622 PMCID:PMC8157730

[180] Kim MY,Kim S,Jeon YK.Clinicopathological analysis of PD-L1 and PD-L2 expression in pulmonary squamous cell carcinoma: comparison with tumor-infiltrating T cells and the status of oncogenic drivers.Lung Cancer2015;88:24-33

[181] Quan H,Wang S.Clinical relevance and significance of programmed death-ligand 1 expression, tumor-infiltrating lymphocytes, and p16 status in sinonasal squamous cell carcinoma.Cancer Manag Res2019;11:4335-45 PMCID:PMC6514258

[182] Bahig H,Stagg J.Phase I/II trial of Durvalumab plus tremelimumab and stereotactic body radiotherapy for metastatic head and neck carcinoma.BMC Cancer2019;19:68 PMCID:PMC6332607

[183] Cavalieri S,Milione M.PD-L1 expression in unresectable locally advanced or metastatic skin squamous cell carcinoma treated with anti-epidermal growth factor receptor agents.Oncology2019;97:112-8

[184] Yanik EL,Cottrell TR.Association of HIV status with local immune response to anal squamous cell carcinoma: implications for immunotherapy.JAMA Oncol2017;3:974-8 PMCID:PMC5696632

[185] Hira-Miyazawa M,Hirai M.Regulation of programmed-death ligand in the human head and neck squamous cell carcinoma microenvironment is mediated through matrix metalloproteinase-mediated proteolytic cleavage.Int J Oncol2018;52:379-88 PMCID:PMC5741372

[186] Yaghoubi N,Ghazvini K,Hashemy SI.PD-1/PD-L1 blockade as a novel treatment for colorectal cancer.Biomed Pharmacother2019;110:312-8

[187] Jahangiri A,Ghorban K.STAT3 inhibition reduced PD-L1 expression and enhanced antitumor immune responses.J Cell Physiol2020;235:9457-63

[188] Li Y,Zhou Y.The prognostic and clinicopathological roles of PD-L1 expression in colorectal cancer: a systematic review and meta-analysis.Front Pharmacol2019;10:139 PMCID:PMC6403169

[189] Hamada T,Qian ZR.Aspirin use and colorectal cancer survival according to tumor CD274 (programmed cell death 1 ligand 1) expression status.J Clin Oncol2017;35:1836-44 PMCID:PMC5455595

[190] Inaguma S,Felisiak-Golabek A.Histopathological and genotypic characterization of metastatic colorectal carcinoma with PD-L1 (CD274)-expression: possible roles of tumour micro environmental factors for CD274 expression.J Pathol Clin Res2017;3:268-78 PMCID:PMC5653930

[191] Masugi Y,Yang J.Tumour CD274 (PD-L1) expression and T cells in colorectal cancer.Gut2017;66:1463-73 PMCID:PMC5097696

[192] Gao CE,Song Q.PD-1 inhibitors dependent CD8⁺ T cells inhibit mouse colon cancer cell metastasis.Onco Targets Ther2019;12:6961-71 PMCID:PMC6717878

[193] Bray F,Soerjomataram I,Torre LA.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2018;68:394-424

[194] Mushtaq J,Nair R.Bladder cancer.Surgery2019;37:529-37

[195] van der Heijden MS,Powles T.Nivolumab plus gemcitabine-cisplatin in advanced urothelial carcinoma.N Engl J Med2023;389:1778-89

[196] Cathomas R,Hayoz S.Perioperative chemoimmunotherapy with durvalumab for muscle-invasive urothelial carcinoma: primary analysis of the single-arm phase II trial SAKK 06/17.J Clin Oncol2023;41:5131-9 PMCID:PMC10666980

[197] Huang YD,McCrudden C,Lin Y.The prognostic significance of PD-L1 in bladder cancer.Oncol Rep2015;33:3075-84

[198] Butte MJ,Kim MJ,Sharpe AH.Interaction of human PD-L1 and B7-1.Mol Immunol2008;45:3567-72 PMCID:PMC3764616

[199] Donin NM,Holden S.Immunotherapy for the treatment of urothelial carcinoma.J Urol2017;197:14-22

[200] Kaufman HL,Hamid O.Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.Lancet Oncol2016;17:1374-85 PMCID:PMC5587154

[201] Atkins MB,Puzanov I.Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial.Lancet Oncol2018;19:405-15

[202] Lipson EJ,Loyo M.PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival.Cancer Immunol Res2013;1:54-63 PMCID:PMC3885978

[203] Ni J,Wang H,Zhang L.Camrelizumab plus platinum-irinotecan followed by maintenance camrelizumab plus apatinib in untreated extensive-stage small-cell lung cancer: a nonrandomized clinical trial.Front Immunol2023;14:1168879 PMCID:PMC10126331

[204] Patil VM,Menon N.Results of phase III randomized trial for use of docetaxel as a radiosensitizer in patients with head and neck cancer, unsuitable for cisplatin-based chemoradiation.J Clin Oncol2023;41:2350-61

[205] O'Shea AE,Qiao N.Phase II trial of nelipepimut-S peptide vaccine in women with ductal carcinoma in situ.Cancer Prev Res2023;16:333-41 PMCID:PMC10903526

[206] Li H,Chen Z.Efficacy and safety of denosumab biosimilar QL1206 versus denosumab in patients with bone metastases from solid tumors: a randomized phase III trial.BioDrugs2023;37:259-69 PMCID:PMC9971153

[207] Penson RT,Whalen CA.Phase II trials of iniparib (BSI-201) in combination with gemcitabine and carboplatin in patients with recurrent ovarian cancer.Oncologist2023;28:252-7 PMCID:PMC10020803

[208] Zheng R,Li Z,Xu B.Combining chemotherapy and tislelizumab with preoperative split-course hypofraction radiotherapy for locally advanced rectal cancer: study protocol of a prospective, single-arm, phase II trial.BMJ Open2023;13:e066976 PMCID:PMC10030573

[209] Topalian SL,Brahmer JR.Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med2012;366:2443-54 PMCID:PMC3544539

[210] Kato T,Nakanishi Y.Nivolumab-induced interstitial lung disease analysis of two phase II studies patients with recurrent or advanced non-small-cell lung cancer.Lung Cancer2017;104:111-8

[211] Jin Y,Xia L.The diversity of gut microbiome is associated with favorable responses to anti-programmed death 1 immunotherapy in Chinese patients with NSCLC.J Thorac Oncol2019;14:1378-89

[212] Ochi N,Takigawa N.The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression.Eur J Cancer2021;149:73-81

[213] Sun LY,Tang WT.Smoking status combined with tumor mutational burden as a prognosis predictor for combination immune checkpoint inhibitor therapy in non-small cell lung cancer.Cancer Med2021;10:6610-7 PMCID:PMC8495280

[214] Zheng Y,Tu X.Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma.J Immunother Cancer2019;7:193 PMCID:PMC6651993

[215] Gopalakrishnan V,Nezi L.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.Science2018;359:97-103

[216] Davar D,McCulloch JA.Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients.Science2021;371:595-602 PMCID:PMC8097968

[217] Baruch EN,Ben-Betzalel G.Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients.Science2021;371:602-9

[218] Dong M,Kuerban K.Diosgenin promotes antitumor immunity and PD-1 antibody efficacy against melanoma by regulating intestinal microbiota.Cell Death Dis2018;9:1039 PMCID:PMC6179990

[219] Burki TK.Gut microbiome and immunotherapy response.Lancet Oncol2017;18:e717

[220] Gut microbes May up PD-1 inhibitor response.Cancer Discov2017;7:448

[221] Nomura M,Doi K.Association of short-chain fatty acids in the gut microbiome with clinical response to treatment with nivolumab or pembrolizumab in patients with solid cancer tumors.JAMA Netw Open2020;3:e202895

[222] Humphries A.The gut microbiota and immune checkpoint inhibitors.Hum Vaccin Immunother2018;14:2178-82 PMCID:PMC6183319

[223] Zhang C,Herrmann A.STAT3 activation-induced fatty acid oxidation in CD8⁺ T effector cells is critical for obesity-promoted breast tumor growth.Cell Metab2020;31:148-61.e5 PMCID:PMC6949402

[224] Pingili AK,Sipe LM.Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer.Cell Rep2021;35:109285 PMCID:PMC8574993

[225] Eden D,Moschetta M,Rassy E.Immunotherapy combined with standard therapies in head and neck squamous cell carcinoma - a meta-analysis.Anticancer Res2024;44:861-78

[226] Rittmeyer A,Waterkamp D.Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.Lancet2017;389:255-65 PMCID:PMC6886121

[227] Nomura S,Mizutani T.A randomized phase III study comparing continuation and discontinuation of PD-1 pathway inhibitors for patients with advanced non-small-cell lung cancer (JCOG1701, SAVE study).Jpn J Clin Oncol2020;50:821-5

[228] Khan U,Khurram MS,Hadid T.Immunotherapy-associated autoimmune hemolytic anemia.J Immunother Cancer2017;5:15 PMCID:PMC5319184

[229] Kunimasa K,Nakamura H.Proliferative CD8⁺ PD-1⁺ T-cell infiltration in a pembrolizumab-induced cutaneous adverse reaction.Invest New Drugs2018;36:1138-42

[230] Zahoor F,Afzal G.Onychopathy induced by nivolumab: a targeted immunotherapy.Cureus2022;14:e26950 PMCID:PMC9381033

[231] Cubillos-Zapata C,Campos-Rodríguez F.Soluble PD-L1 is a potential biomarker of cutaneous melanoma aggressiveness and metastasis in obstructive sleep apnoea patients.Eur Respir J2019;53:1801298

[232] Huang X,Li X.Rescue of iCIKs transfer from PD-1/PD-L1 immune inhibition in patients with resectable tongue squamous cell carcinoma (TSCC).Int Immunopharmacol2018;59:127-33

[233] Stenmark Tullberg A,Tran L.Combining histological grade, TILs, and the PD-1/PD-L1 pathway to identify immunogenic tumors and de-escalate radiotherapy in early breast cancer: a secondary analysis of a randomized clinical trial.J Immunother Cancer2023;11:e006618 PMCID:PMC10201214

[234] Eichhorn F,Bischoff H.Neoadjuvant anti-programmed Death-1 immunotherapy by Pembrolizumab in resectable nodal positive stage II/IIIa non-small-cell lung cancer (NSCLC): the NEOMUN trial.BMC Cancer2019;19:413 PMCID:PMC6498462

[235] Piersiala K,Hjalmarsson E.CD4⁺ and CD8⁺ T cells in sentinel nodes exhibit distinct pattern of PD-1, CD69, and HLA-DR expression compared to tumor tissue in oral squamous cell carcinoma.Cancer Sci2021;112:1048-59 PMCID:PMC7935788

[236] Miyoshi Y,Oyama Y.Nivolumab, an anti-programmed cell death-1 antibody, induces fulminant type 1 diabetes.Tohoku J Exp Med2016;239:155-8

[237] Vienot A,Rebucci-Peixoto M.Evaluation of the interest to combine a CD4 Th1-inducer cancer vaccine derived from telomerase and atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: a randomized non-comparative phase II study (TERTIO - PRODIGE 82).BMC Cancer2023;23:710 PMCID:PMC10387199

[238] Yun SJ,Park CK.Vitiligo-like depigmentation after pembrolizumab treatment in patients with non-small cell lung cancer: a case report.Transl Lung Cancer Res2020;9:1585-90 PMCID:PMC7481606

[239] Kunimasa K,Kimura M.Pembrolizumab-induced acute thrombosis: a case report.Medicine2018;97:e10772 PMCID:PMC5976311

[240] Cui G,Bai Y,Li Y.Postoperative pathological complete response in a patient with PD-L1-negative stage IIIB lung squamous cell carcinoma following neoadjuvant tislelizumab treatment combined with chemotherapy: a case report and literature review.Oncol Lett2023;26:388 PMCID:PMC10407863

[241] Merhi M,Inchakalody VP.Squamous cell carcinomas of the head and neck cancer response to programmed cell death protein-1 targeting and differential expression of immunological markers: a case report.Front Immunol2018;9:1769 PMCID:PMC6079623

[242] Ribas A,Daud A.Association of pembrolizumab with tumor response and survival among patients with advanced melanoma.JAMA2016;315:1600-9

[243] Pazoki-Toroudi HR,Habibey R.Pre-medication and renal pre-conditioning: a role for alprazolam, atropine, morphine and promethazine.Fundam Clin Pharmacol2010;24:189-98

[244] Habibey R.Morphine dependence protects rat kidney against ischaemia-reperfusion injury.Clin Exp Pharmacol Physiol2008;35:1209-14

[245] Shoorei H,Kebria MM.Hesperidin improves the follicular development in 3D culture of isolated preantral ovarian follicles of mice.Exp Biol Med2019;244:352-61 PMCID:PMC6488865