{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPDCD1, the gene encoding the programmed cell death‐1 (PD‑1) receptor, serves as a central “rheostat” that modulates immune activation and maintains peripheral tolerance. Upon antigen encounter and T‐cell receptor engagement, PD‑1 is rapidly induced on T cells, where its interaction with ligands PD‑L1 and PD‑L2 attenuates downstream signaling pathways—including PI3K–Akt, cell cycle progression, and cytokine production—to limit effector functions. This inhibitory signaling not only curbs overzealous responses that might otherwise lead to autoimmunity (as illustrated in autoimmune conditions and models of systemic lupus erythematosus) but also contributes to programmed T‐cell exhaustion in chronic infections such as HIV, hepatitis B and C, and during sustained antigen exposure. Studies further implicate PD‑1 in reprogramming T‐cell metabolism toward increased fatty acid oxidation and in epigenetically imprinting an “exhausted” state via the upregulation of inhibitory transcriptional regulators."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the tumor microenvironment, PD‑1 is frequently exploited to enable immune evasion. Many cancers upregulate PD‑L1 either intrinsically (via oncogenic signals or structural alterations) or adaptively in response to interferon‐γ, leading to engagement of PD‑1 on tumor‐infiltrating lymphocytes and thereby suppressing their cytotoxic responses. Beyond its classical role on T cells, PD‑1 expression has also been detected on other immune cells—including natural killer cells and even within tumor cells themselves—further contributing to an immunosuppressive milieu. The resulting impairment of antitumor immunity has provided the rationale for therapies targeting PD‑1 or its ligands, a strategy that underlies the remarkable clinical responses observed in multiple malignancies such as head and neck, lung, and hematologic cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging insights further reveal that the PD‑1 pathway not only dictates intercellular immune crosstalk but also influences intrinsic cellular functions that affect therapy outcomes. Recent work has demonstrated that PD‑1 expression can serve as a biomarker—identifying neoantigen‐specific lymphocytes in peripheral blood—and that blockade of PD‑1 can reinvigorate exhausted T cells, restore metabolic programs, and even enhance the efficacy of adoptive cellular therapies. These findings have spurred the development of combinatorial treatment strategies (for example, integrating PD‑1 inhibition with PARP inhibition or chimeric antigen receptor engineering) and have broadened the clinical relevance of targeting PD‑1 across diverse settings, including sepsis and other dysregulated immune states."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ludmila Prokunina, Casimiro Castillejo-López, Fredrik Oberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1020"}], "href": "https://doi.org/10.1038/ng1020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12402038"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12402038"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Richard V Parry, Jens M Chemnitz, Kenneth A Frauwirth, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.25.21.9543-9553.2005"}], "href": "https://doi.org/10.1128/MCB.25.21.9543-9553.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16227604"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16227604"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Lydie Trautmann, Loury Janbazian, Nicolas Chomont, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm1482"}], "href": "https://doi.org/10.1038/nm1482"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16917489"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16917489"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Constantinos Petrovas, Joseph P Casazza, Jason M Brenchley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20061496"}], "href": "https://doi.org/10.1084/jem.20061496"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16954372"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16954372"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Simona Urbani, Barbara Amadei, Daniela Tola, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/JVI.01177-06"}], "href": "https://doi.org/10.1128/JVI.01177-06"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16956940"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16956940"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Mary E Keir, Manish J Butte, Gordon J Freeman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PD-1 and its ligands in tolerance and immunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Annu Rev Immunol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1146/annurev.immunol.26.021607.090331"}], "href": "https://doi.org/10.1146/annurev.immunol.26.021607.090331"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18173375"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18173375"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Audrey L Kinter, Emily J Godbout, Jonathan P McNally, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.181.10.6738"}], "href": "https://doi.org/10.4049/jimmunol.181.10.6738"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18981091"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18981091"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Mojgan Ahmadzadeh, Laura A Johnson, Bianca Heemskerk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2008-12-195792"}], "href": "https://doi.org/10.1182/blood-2008-12-195792"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19423728"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19423728"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Paola Fisicaro, Caterina Valdatta, Marco Massari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2009.09.052"}], "href": "https://doi.org/10.1053/j.gastro.2009.09.052"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19800335"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19800335"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Feng Shi, Ming Shi, Zhen Zeng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.25397"}], "href": "https://doi.org/10.1002/ijc.25397"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20473887"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20473887"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Loise M Francisco, Peter T Sage, Arlene H Sharpe "}, {"type": "b", "children": [{"type": "t", "text": "The PD-1 pathway in tolerance and autoimmunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunol Rev (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1600-065X.2010.00923.x"}], "href": "https://doi.org/10.1111/j.1600-065X.2010.00923.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20636820"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20636820"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Julien Fourcade, Zhaojun Sun, Mourad Benallaoua, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20100637"}], "href": "https://doi.org/10.1084/jem.20100637"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20819923"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20819923"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Michael Quigley, Florencia Pereyra, Björn Nilsson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.2232"}], "href": "https://doi.org/10.1038/nm.2232"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20890291"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20890291"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Ben Youngblood, Kenneth J Oestreich, Sang-Jun Ha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8(+) T cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunity (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.immuni.2011.06.015"}], "href": "https://doi.org/10.1016/j.immuni.2011.06.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21943489"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21943489"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Shoba Amarnath, Courtney W Mangus, James C M Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The PDL1-PD1 axis converts human TH1 cells into regulatory T cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Transl Med (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scitranslmed.3003130"}], "href": "https://doi.org/10.1126/scitranslmed.3003130"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22133721"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22133721"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Nikolaos Patsoukis, Julia Brown, Victoria Petkova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.2002796"}], "href": "https://doi.org/10.1126/scisignal.2002796"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22740686"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22740686"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Sofia Lyford-Pike, Shiwen Peng, Geoffrey D Young, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-12-2384"}], "href": "https://doi.org/10.1158/0008-5472.CAN-12-2384"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23288508"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23288508"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Michela Locci, Colin Havenar-Daughton, Elise Landais, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunity (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.immuni.2013.08.031"}], "href": "https://doi.org/10.1016/j.immuni.2013.08.031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24035365"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24035365"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Philippe Armand, Arnon Nagler, Edie A Weller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2012.48.3685"}], "href": "https://doi.org/10.1200/JCO.2012.48.3685"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24127452"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24127452"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Janis M Taube, Alison Klein, Julie R Brahmer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-13-3271"}], "href": "https://doi.org/10.1158/1078-0432.CCR-13-3271"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24714771"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24714771"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "A D'Incecco, M Andreozzi, V Ludovini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/bjc.2014.555"}], "href": "https://doi.org/10.1038/bjc.2014.555"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25349974"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25349974"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Naiyer A Rizvi, Julien Mazières, David Planchard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Lancet Oncol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S1470-2045(15)70054-9"}], "href": "https://doi.org/10.1016/S1470-2045(15"}, {"type": "t", "text": "70054-9) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25704439"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25704439"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Joe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI80445"}], "href": "https://doi.org/10.1172/JCI80445"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25866972"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25866972"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Nikolaos Patsoukis, Kankana Bardhan, Pranam Chatterjee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms7692"}], "href": "https://doi.org/10.1038/ncomms7692"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25809635"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25809635"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Sonja Kleffel, Christian Posch, Steven R Barthel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2015.08.052"}], "href": "https://doi.org/10.1016/j.cell.2015.08.052"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26359984"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26359984"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Kristin J Lastwika, Willie Wilson, Qing Kay Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-14-3362"}], "href": "https://doi.org/10.1158/0008-5472.CAN-14-3362"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26637667"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26637667"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "S Champiat, O Lambotte, E Barreau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Oncol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/annonc/mdv623"}], "href": "https://doi.org/10.1093/annonc/mdv623"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26715621"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26715621"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Alena Gros, Maria R Parkhurst, Eric Tran, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.4051"}], "href": "https://doi.org/10.1038/nm.4051"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26901407"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26901407"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Keisuke Kataoka, Yuichi Shiraishi, Yohei Takeda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature18294"}], "href": "https://doi.org/10.1038/nature18294"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27281199"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27281199"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Philippe Armand, Margaret A Shipp, Vincent Ribrag, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2016.67.3467"}], "href": "https://doi.org/10.1200/JCO.2016.67.3467"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27354476"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27354476"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Silvia Pesce, Marco Greppi, Giovanna Tabellini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Allergy Clin Immunol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jaci.2016.04.025"}], "href": "https://doi.org/10.1016/j.jaci.2016.04.025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27372564"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27372564"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Leonid Cherkassky, Aurore Morello, Jonathan Villena-Vargas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI83092"}], "href": "https://doi.org/10.1172/JCI83092"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27454297"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27454297"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "J C Osorio, A Ni, J E Chaft, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Oncol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/annonc/mdw640"}], "href": "https://doi.org/10.1093/annonc/mdw640"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27998967"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27998967"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Zhong-Yi Dong, Wen-Zhao Zhong, Xu-Chao Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Potential Predictive Value of "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "TP53"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " and "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "KRAS"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-16-2554"}], "href": "https://doi.org/10.1158/1078-0432.CCR-16-2554"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28039262"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28039262"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Shiping Jiao, Weiya Xia, Hirohito Yamaguchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-16-3215"}], "href": "https://doi.org/10.1158/1078-0432.CCR-16-3215"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28167507"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28167507"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Whijae Roh, Pei-Ling Chen, Alexandre Reuben, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Transl Med (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scitranslmed.aah3560"}], "href": "https://doi.org/10.1126/scitranslmed.aah3560"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28251903"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28251903"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "E Saâda-Bouzid, C Defaucheux, A Karabajakian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Oncol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/annonc/mdx178"}], "href": "https://doi.org/10.1093/annonc/mdx178"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28419181"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28419181"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Jennifer H Yearley, Christopher Gibson, Ni Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-16-1761"}], "href": "https://doi.org/10.1158/1078-0432.CCR-16-1761"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28619999"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28619999"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Aaron M Goodman, Shumei Kato, Lyudmila Bazhenova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Ther (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1535-7163.MCT-17-0386"}], "href": "https://doi.org/10.1158/1535-7163.MCT-17-0386"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28835386"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28835386"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Ziming Wang, Ethan G Aguilar, Jesus I Luna, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41591-018-0221-5"}], "href": "https://doi.org/10.1038/s41591-018-0221-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30420753"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30420753"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Pengfei Zhao, Li Li, Xiaoyue Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hematol Oncol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13045-019-0738-1"}], "href": "https://doi.org/10.1186/s13045-019-0738-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31151482"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31151482"}]}]}]}