PD-L2 is a second ligand for PD-1 and inhibits T cell activation
Abstract
Programmed death I (PD-I)-deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identify here PD-1 ligand 2 (PD-L2) as a second ligand for PD-1 and compare the function and expression of PD-L1 and PD-L2. Engagement of PD-1 by PD-L2 dramatically inhibits T cell receptor (TCR)-mediated proliferation and cytokine production by CD4+ T cells. At low antigen concentrations, PD-L2-PD-1 interactions inhibit strong B7-CD28 signals. In contrast, at high antigen concentrations, PD-L2-PD-1 interactions reduce cytokine production but do not inhibit T cell proliferation. PD-L-PD-1 interactions lead to cell cycle arrest in G0/G1 but do not increase cell death. In addition, ligation of PD-1 + TCR leads to rapid phosphorylation of SHP-2, as compared to TCR ligation alone. PD-L expression was up-regulated on antigen-presenting cells by interferon gamma treatment and was also present on some normal tissues and tumor cell lines. Taken together, these studies show overlapping functions of PD-L1 and PD-L2 and indicate a key role for the PD-L-PD-1 pathway in regulatingT cell responses.
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PD-L1 is highly expressed in inflamed cells.
“(4)PD-L1 is highly expressed in inflamed cells and PD-L2 is expressed only in antigen-presenting cells [230].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [230]
PD-L2 is expressed only in antigen-presenting cells.
“(4)PD-L1 is highly expressed in inflamed cells and PD-L2 is expressed only in antigen-presenting cells [230].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [230]
PD-L1 and PD-L2 are found on antigen-presenting cells and differentially expressed on various non-lymphoid tissues.
“Both can be found on the surface of antigen-presenting cells (such as dendritic cells, macrophages, and monocytes), but are otherwise differentially expressed on various non-lymphoid tissues (39, 40).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [39]
PD-1 activity is only relevant during simultaneous T cell activation, as its signal transduction only comes into effect during TCR-dependent signaling.
“PD-1 activity is therefore only relevant during simultaneous T cell activation, as its signal transduction can only come into effect during TCR-dependent signaling (39, 41, 48).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [39]
PD-1 interaction with PD-L1 and PD-L2 can diminish immune responses.
“Upon interaction with its ligands, programmed death-ligand 1 (PD-L1; a.k.a. B7-H1 or CD274) and PD-L2 (a.k.a. B7-DC or CD273), it can diminish immune responses (Freeman et al., 2000; Latchman et al., 2001).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Latchman et al., 2001
PD-L1 and PD-L2 are expressed on hematopoietic and nonhematopoietic cells, including APCs and cancer cells.
“Both PD-L1 and PD-L2 are expressed on hematopoietic and nonhematopoietic cells, including APCs and cancer cells (36,37).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [37]
Engagement of PD-1 with PD-L1 or PD-L2 suppresses T cell immune responses.
“Similar to CTLA-4, engagement of PD-1 with its ligands, PD-L1 and PD-L2, leads to suppression of T cell immune responses (36,37).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [37]
Cites
Lymphoproliferative Disorders with Early Lethality in Mice Deficient in <i>Ctla-4</i>
Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., Thompson, C. B., Griesser, H., & Mak, T. W. (1995) · Science · doi:10.1126/science.270.5238.985 · Cited by 2,766 · see citing works
Regulation of Cytotoxic T Lymphocyte-Associated Molecule-4 by Src Kinases
Chuang, E., Lee, K.-M., Robbins, M. D., Duerr, J. M., Alegre, M.-L., Hambor, J. E., Neveu, M. J., Bluestone, J. A., & Thompson, C. B. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.3.1270 · Cited by 119 · see citing works
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The blockade of immune checkpoints in cancer immunotherapy
Pardoll, D. M. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3239 · Cited by 13,838 · see citing works
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer
Brahmer, J. R., Tykodi, S. S., Chow, L. Q. M., Hwu, W.-J., Topalian, S. L., Hwu, P., Drake, C. G., Camacho, L. H., Kauh, J., Odunsi, K., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200694 · Cited by 7,945 · see citing works
“All squamous type All doses 13 1 8 (0-36) ND 3 23 (5-54) 43 (15-71)”
InfluentialPD-1 and Its Ligands in Tolerance and Immunity
Keir, M. E., Butte, M. J., Freeman, G. J., & Sharpe, A. H. (2008) · Annual Review of Immunology · doi:10.1146/annurev.immunol.26.021607.090331 · Cited by 5,378 · see citing works
Self-citationImmune Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy
Topalian, S. L., Drake, C. G., & Pardoll, D. M. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.03.001 · Cited by 4,229 · see citing works
A guide to cancer immunotherapy: from T cell basic science to clinical practice
Waldman, A. D., Fritz, J. M., & Lenardo, M. J. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0306-5 · Cited by 4,154 · see citing works
Rosenberg, J. E., Hoffman-Censits, J., Powles, T., van der Heijden, M. S., Balar, A. V., Necchi, A., Dawson, N., O'Donnell, P. H., Balmanoukian, A., Loriot, Y., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)00561-4 · Cited by 3,669 · see citing works
Fehrenbacher, L., Spira, A., Ballinger, M., Kowanetz, M., Vansteenkiste, J., Mazieres, J., Park, K., Smith, D., Artal-Cortes, A., Lewanski, C., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)00587-0 · Cited by 2,756 · see citing works
PD-L1 expression as a predictive biomarker in cancer immunotherapy
Patel, S. P., & Kurzrock, R. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0983 · Cited by 2,291 · see citing works
Bagchi, S., Yuan, R., & Engleman, E. G. (2021) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-042020-042741 · Cited by 2,189 · see citing works
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R., Kuchroo, V. K., & Anderson, A. C. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100643 · Cited by 2,072 · see citing works
Hallmarks of response, resistance, and toxicity to immune checkpoint blockade
Morad, G., Helmink, B. A., Sharma, P., & Wargo, J. A. (2021) · Cell · doi:10.1016/j.cell.2021.09.020 · Cited by 1,648 · see citing works
Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer
Costa, A., Kieffer, Y., Scholer-Dahirel, A., Pelon, F., Bourachot, B., Cardon, M., Sirven, P., Magagna, I., Fuhrmann, L., Bernard, C., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.01.011 · Cited by 1,705 · see citing works
Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction
Trautmann, L., Janbazian, L., Chomont, N., Said, E. A., Gimmig, S., Bessette, B., Boulassel, M.-R., Delwart, E., Sepulveda, H., Balderas, R. S., et al. (2006) · Nature Medicine · doi:10.1038/nm1482 · Cited by 1,565 · see citing works
Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations
Seidel, J. A., Otsuka, A., & Kabashima, K. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00086 · Cited by 1,360 · see citing works
The Liver as an Immunological Organ
Racanelli, V., & Rehermann, B. (2006) · Hepatology · doi:10.1002/hep.21060 · Cited by 1,377 · see citing works
Hamanishi, J., Mandai, M., Iwasaki, M., Okazaki, T., Tanaka, Y., Yamaguchi, K., Higuchi, T., Yagi, H., Takakura, K., Minato, N., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611533104 · Cited by 1,378 · see citing works
Self-citationPD-1 and PD-1 ligands: from discovery to clinical application
Okazaki, T., & Honjo, T. (2007) · International Immunology · doi:10.1093/intimm/dxm057 · Cited by 1,310 · see citing works
Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade
Wei, S. C., Levine, J. H., Cogdill, A. P., Zhao, Y., Anang, N.-A. A. S., Andrews, M. C., Sharma, P., Wang, J., Wargo, J. A., Pe’er, D., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.024 · Cited by 1,302 · see citing works
Yokosuka, T., Takamatsu, M., Kobayashi-Imanishi, W., Hashimoto-Tane, A., Azuma, M., & Saito, T. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20112741 · Cited by 1,161 · see citing works
Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity
Hirano, F., Kaneko, K., Tamura, H., Dong, H., Wang, S., Ichikawa, M., Rietz, C., Flies, D. B., Lau, J. S., Zhu, G., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.1089.65.3 · Cited by 1,018 · see citing works
Brown, J. A., Dorfman, D. M., Ma, F.-R., Sullivan, E. L., Munoz, O., Wood, C. R., Greenfield, E. A., & Freeman, G. J. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.3.1257 · Cited by 968 · see citing works
Self-citationNomi, T., Sho, M., Akahori, T., Hamada, K., Kubo, A., Kanehiro, H., Nakamura, S., Enomoto, K., Yagita, H., Azuma, M., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2746 · Cited by 889 · see citing works
BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1
Watanabe, N., Gavrieli, M., Sedy, J. R., Yang, J., Fallarino, F., Loftin, S. K., Hurchla, M. A., Zimmerman, N., Sim, J., Zang, X., et al. (2003) · Nature Immunology · doi:10.1038/ni944 · Cited by 883 · see citing works
PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection
Petrovas, C., Casazza, J. P., Brenchley, J. M., Price, D. A., Gostick, E., Adams, W. C., Precopio, M. L., Schacker, T., Roederer, M., Douek, D. C., et al. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20061496 · Cited by 889 · see citing works
Sheppard, K.-A., Fitz, L. J., Lee, J. M., Benander, C., George, J. A., Wooters, J., Qiu, Y., Jussif, J. M., Carter, L. L., Wood, C. R., et al. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.07.083 · Cited by 791 · see citing works
Self-citationOhigashi, Y., Sho, M., Yamada, Y., Tsurui, Y., Hamada, K., Ikeda, N., Mizuno, T., Yoriki, R., Kashizuka, H., Yane, K., et al. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-1469 · Cited by 796 · see citing works
PD-1 signaling in primary T cells
Riley, J. L. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2009.00767.x · Cited by 778 · see citing works
Cancer immunotherapy—immune checkpoint blockade and associated endocrinopathies.
Byun, D. J., Wolchok, J. D., Rosenberg, L. M., & Girotra, M. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.205 · Cited by 685 · see citing works
Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure)
Kim, J. M., & Chen, D. S. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw217 · Cited by 648 · see citing works
Clinical Significance of PD-L1+ Exosomes in Plasma of Head and Neck Cancer Patients
Theodoraki, M.-N., Yerneni, S. S., Hoffmann, T. K., Gooding, W. E., & Whiteside, T. L. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2664 · Cited by 624 · see citing works
Becht, E., de Reyniès, A., Giraldo, N. A., Pilati, C., Buttard, B., Lacroix, L., Selves, J., Sautès-Fridman, C., Laurent-Puig, P., & Fridman, W. H. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2879 · Cited by 590 · see citing works
PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer
Yearley, J. H., Gibson, C., Yu, N., Moon, C., Murphy, E., Juco, J., Lunceford, J., Cheng, J., Chow, L. Q. M., Seiwert, T. Y., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1761 · Cited by 594 · see citing works
The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation
Bardhan, K., Anagnostou, T., & Boussiotis, V. A. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00550 · Cited by 606 · see citing works
Self-citationThe B7 family member B7-H3 preferentially down-regulates T helper type 1–mediated immune responses
Suh, W.-K., Gajewska, B. U., Okada, H., Gronski, M. A., Bertram, E. M., Dawicki, W., Duncan, G. S., Bukczynski, J., Plyte, S., Elia, A., et al. (2003) · Nature Immunology · doi:10.1038/ni967 · Cited by 576 · see citing works
Dustin, M. L. (2014) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0161 · Cited by 502 · see citing works
Patsoukis, N., Brown, J., Petkova, V., Liu, F., Li, L., & Boussiotis, V. A. (2012) · Science Signaling · doi:10.1126/scisignal.2002796 · Cited by 529 · see citing works
Self-citationStrioga, M., Pasukoniene, V., & Characiejus, D. (2011) · Immunology · doi:10.1111/j.1365-2567.2011.03470.x · Cited by 505 · see citing works
Kinter, A. L., Godbout, E. J., McNally, J. P., Sereti, I., Roby, G. A., O’Shea, M. A., & Fauci, A. S. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.10.6738 · Cited by 513 · see citing works
Nakanishi, J., Wada, Y., Matsumoto, K., Azuma, M., Kikuchi, K., & Ueda, S. (2007) · Cancer Immunology, Immunotherapy · doi:10.1007/s00262-006-0266-z · Cited by 473 · see citing works
PD‐1/PD‐L1 pathway: Basic biology and role in cancer immunotherapy
Salmaninejad, A., Valilou, S. F., Shabgah, A. G., Aslani, S., Alimardani, M., Pasdar, A., & Sahebkar, A. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28358 · Cited by 445 · see citing works
Role of the PD-1 pathway in the immune response
Riella, L. V., Paterson, A. M., Sharpe, A. H., & Chandraker, A. (2012) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2012.04224.x · Cited by 444 · see citing works
“IL-4 and GM CSF are the strongest known stimuli for inducing PD-L2 expression (5,12,19,23,24).”
BackgroundInfluentialSelf-citationHDAC Inhibition Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy with PD-1 Blockade
Woods, D. M., Sodré, A. L., Villagra, A., Sarnaik, A., Sotomayor, E. M., & Weber, J. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0077-t · Cited by 454 · see citing works
Baessler, A., & Vignali, D. A. A. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-090222-110914 · Cited by 420 · see citing works
Bour‐Jordan, H., Esensten, J. H., Martinez‐Llordella, M., Penaranda, C., Stumpf, M., & Bluestone, J. A. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01011.x · Cited by 391 · see citing works
Immune modulation by mesenchymal stem cells
Rasmusson, I. (2006) · Experimental Cell Research · doi:10.1016/j.yexcr.2006.03.019 · Cited by 374 · see citing works
Mühlbauer, M., Fleck, M., Schütz, C., Weiss, T., Froh, M., Blank, C., Schölmerich, J., & Hellerbrand, C. (2006) · Journal of Hepatology · doi:10.1016/j.jhep.2006.05.007 · Cited by 378 · see citing works
Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses
Liu, J., Yuan, Y., Chen, W., Putra, J., Suriawinata, A. A., Schenk, A. D., Miller, H. E., Guleria, I., Barth, R. J., Huang, Y. H., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1420370112 · Cited by 374 · see citing works
PD-1 is a novel regulator of human B-cell activation
Thibult, M.-L., Mamessier, E., Gertner-Dardenne, J., Pastor, S., Just-Landi, S., Xerri, L., Chetaille, B., & Olive, D. (2013) · International Immunology · doi:10.1093/intimm/dxs098 · Cited by 365 · see citing works
Constantinidou, A., Alifieris, C., & Trafalis, D. T. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.09.008 · Cited by 342 · see citing works
Verma, V., Shrimali, R. K., Ahmad, S., Dai, W., Wang, H., Lu, S., Nandre, R., Gaur, P., Lopez, J., Sade-Feldman, M., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0441-y · Cited by 333 · see citing works
The immune system and cancer evasion strategies: therapeutic concepts
Muenst, S., Läubli, H., Soysal, S. D., Zippelius, A., Tzankov, A., & Hoeller, S. (2016) · Journal of Internal Medicine · doi:10.1111/joim.12470 · Cited by 304 · see citing works
Blockade of PD‐L1 (B7‐H1) augments human tumor‐specific T cell responses <i>in vitro</i>
Blank, C., Kuball, J., Voelkl, S., Wiendl, H., Becker, B., Walter, B., Majdic, O., Gajewski, T. F., Theobald, M., Andreesen, R., et al. (2006) · International Journal of Cancer · doi:10.1002/ijc.21775 · Cited by 297 · see citing works
Diehl, L., Schurich, A., Grochtmann, R., Hegenbarth, S., Chen, L., & Knolle, P. A. (2008) · Hepatology · doi:10.1002/hep.21965 · Cited by 291 · see citing works
Obesity accelerates T cell senescence in murine visceral adipose tissue
Shirakawa, K., Yan, X., Shinmura, K., Endo, J., Kataoka, M., Katsumata, Y., Yamamoto, T., Anzai, A., Isobe, S., Yoshida, N., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci88606 · Cited by 271 · see citing works
Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy
Lee, N., Zakka, L. R., Mihm, M. C., & Schatton, T. (2016) · Pathology · doi:10.1016/j.pathol.2015.12.006 · Cited by 250 · see citing works
Current and emerging therapeutic approaches for colorectal cancer: A comprehensive review
Kumar, A., Gautam, V., Sandhu, A., Rawat, K., Sharma, A., & Saha, L. (2023) · World Journal of Gastrointestinal Surgery · doi:10.4240/wjgs.v15.i4.495 · Cited by 272 · see citing works
Nazareth, M. R., Broderick, L., Simpson-Abelson, M. R., Kelleher, R. J., Yokota, S. J., & Bankert, R. B. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.9.5552 · Cited by 259 · see citing works
Immune checkpoint inhibitor–associated myocarditis: manifestations and mechanisms
Moslehi, J., Lichtman, A. H., Sharpe, A. H., Galluzzi, L., & Kitsis, R. N. (2021) · Journal of Clinical Investigation · doi:10.1172/jci145186 · Cited by 237 · see citing works
Self-citationB7-H1-Induced Apoptosis as a Mechanism of Immune Privilege of Corneal Allografts
Hori, J., Wang, M., Miyashita, M., Tanemoto, K., Takahashi, H., Takemori, T., Okumura, K., Yagita, H., & Azuma, M. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.9.5928 · Cited by 208 · see citing works
Subrahmanyam, P. B., Dong, Z., Gusenleitner, D., Giobbie-Hurder, A., Severgnini, M., Zhou, J., Manos, M., Eastman, L. M., Maecker, H. T., & Hodi, F. S. (2018) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0328-8 · Cited by 190 · see citing works
Dovedi, S. J., Elder, M. J., Yang, C., Sitnikova, S. I., Irving, L., Hansen, A., Hair, J., Jones, D. C., Hasani, S., Wang, B., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1445 · Cited by 186 · see citing works
PD-1 expression on dendritic cells suppresses CD8<sup>+</sup>T cell function and antitumor immunity
Lim, T. S., Chew, V., Sieow, J. L., Goh, S., Yeong, J. P.-S., Soon, A. L., & Ricciardi-Castagnoli, P. (2016) · OncoImmunology · doi:10.1080/2162402x.2015.1085146 · Cited by 184 · see citing works
David, J. M., Dominguez, C., McCampbell, K. K., Gulley, J. L., Schlom, J., & Palena, C. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1349589 · Cited by 180 · see citing works
Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study
Yamauchi, I., Sakane, Y., Fukuda, Y., Fujii, T., Taura, D., Hirata, M., Hirota, K., Ueda, Y., Kanai, Y., Yamashita, Y., et al. (2017) · Thyroid · doi:10.1089/thy.2016.0562 · Cited by 169 · see citing works
Shp-2 Is Dispensable for Establishing T Cell Exhaustion and for PD-1 Signaling In Vivo
Rota, G., Niogret, C., Dang, A. T., Barros, C. R., Fonta, N. P., Alfei, F., Morgado, L., Zehn, D., Birchmeier, W., Vivier, E., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.026 · Cited by 155 · see citing works
Yin–Yang of costimulation: crucial controls of immune tolerance and function
Nurieva, R. I., Liu, X., & Dong, C. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2009.00769.x · Cited by 157 · see citing works
Zheng, B., Ren, T., Huang, Y., Sun, K., Wang, S., Bao, X., Liu, K., & Guo, W. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0560-1 · Cited by 151 · see citing works
Heavy chain ferritin activates regulatory T cells by induction of changes in dendritic cells
Gray, C. P., Arosio, P., & Hersey, P. (2002) · Blood · doi:10.1182/blood.v99.9.3326 · Cited by 118 · see citing works
The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2
Chaib, S., López-Domínguez, J. A., Lalinde-Gutiérrez, M., Prats, N., Marin, I., Boix, O., García-Garijo, A., Meyer, K., Muñoz, M. I., Aguilera, M., et al. (2024) · Nature Cancer · doi:10.1038/s43018-023-00712-x · Cited by 114 · see citing works
Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor Mutant
Pascolutti, R., Sun, X., Kao, J., Maute, R. L., Ring, A. M., Bowman, G. R., & Kruse, A. C. (2016) · Structure · doi:10.1016/j.str.2016.06.026 · Cited by 102 · see citing works
Exosomal PD‐L1: New Insights Into Tumor Immune Escape Mechanisms and Therapeutic Strategies
Zhou, K., Guo, S., Li, F., Sun, Q., & Liang, G. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.569219 · Cited by 99 · see citing works
Affinity purification mass spectrometry analysis of PD-1 uncovers SAP as a new checkpoint inhibitor
Peled, M., Tocheva, A. S., Sandigursky, S., Nayak, S., Philips, E. A., Nichols, K. E., Strazza, M., Azoulay-Alfaguter, I., Askenazi, M., Neel, B. G., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710437115 · Cited by 87 · see citing works
Increased PD-1 expression on CD4+ and CD8+ T cells is involved in immune evasion in gastric cancer
Saito, H., Kuroda, H., Matsunaga, T., Osaki, T., & Ikeguchi, M. (2013) · Journal of Surgical Oncology · doi:10.1002/jso.23281 · Cited by 94 · see citing works
Kudo, M. (2019) · Liver Cancer · doi:10.1159/000503254 · Cited by 70 · see citing works
PD-1 coinhibitory signals: the link between pathogenesis and protection
Kulpa, D. A., Lawani, M., Cooper, A., Peretz, Y., Ahlers, J., & Sékaly, R.-P. (2013) · Seminars in Immunology · doi:10.1016/j.smim.2013.02.002 · Cited by 70 · see citing works
Aguirre, L. E., Guzman, M. E., Lopes, G., & Hurley, J. (2019) · The Oncologist · doi:10.1634/theoncologist.2018-0195 · Cited by 68 · see citing works
Small molecules targeting protein–protein interactions for cancer therapy
Wu, D., Li, Y., Zheng, L., Xiao, H., Ouyang, L., Wang, G., & Sun, Q. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.05.035 · Cited by 71 · see citing works
PD-1 Imposes Qualitative Control of Cellular Transcriptomes in Response to T Cell Activation
Shimizu, K., Sugiura, D., Okazaki, I.-M., Maruhashi, T., Takegami, Y., Cheng, C., Ozaki, S., & Okazaki, T. (2020) · Molecular Cell · doi:10.1016/j.molcel.2019.12.012 · Cited by 63 · see citing works
Self-citationImmune checkpoint inhibitors associated cardiovascular immune-related adverse events
Jo, W., Won, T., Daoud, A., & Čiháková, D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1340373 · Cited by 55 · see citing works
Healthy but not RSV-infected lung epithelial cells profoundly inhibit T cell activation
Wang, H., Su, Z., & Schwarze, J. (2009) · Thorax · doi:10.1136/thx.2007.094870 · Cited by 39 · see citing works
Immune checkpoint inhibitors for multiple myeloma immunotherapy
Liu, Z., Xu, X., Liu, H., Zhao, X., Yang, C., & Fu, R. (2023) · Experimental Hematology & Oncology · doi:10.1186/s40164-023-00456-5 · Cited by 40 · see citing works
Peptide‐based targeted therapeutics and apoptosis imaging probes for cancer therapy
Vadevoo, S. M. P., Gurung, S., Khan, F., Haque, M. E., Gunassekaran, G. R., Chi, L., Permpoon, U., & Lee, B. (2019) · Archives of Pharmacal Research · doi:10.1007/s12272-019-01125-0 · Cited by 38 · see citing works
Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy
Nikolouzakis, T. K., Chrysos, E., Docea, A. O., Fragkiadaki, P., Souglakos, J., Tsiaoussis, J., & Tsatsakis, A. (2024) · Cancers · doi:10.3390/cancers16111995 · Cited by 37 · see citing works
Immunotherapy Resistance in Glioblastoma
Wang, E. J., Chen, J.-S., Jain, S., Morshed, R. A., Haddad, A. F., Gill, S., Beniwal, A. S., & Aghi, M. K. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.750675 · Cited by 34 · see citing works
Cox, M., Kartikasari, A. E. R., Gorry, P. R., Flanagan, K. L., & Plebanski, M. (2021) · Biomedicines · doi:10.3390/biomedicines9040351 · Cited by 30 · see citing works
Cramer, M. L., Shao, G., Rodino-Klapac, L. R., Chicoine, L. G., & Martin, P. T. (2017) · Human Gene Therapy · doi:10.1089/hum.2016.113 · Cited by 22 · see citing works
Seethapathy, H., Mistry, K., & Sise, M. E. (2023) · Immunological Reviews · doi:10.1111/imr.13243 · Cited by 15 · see citing works
- Authors
- Latchman, Y., Wood, C. R., Chernova, T., Chaudhary, D., Borde, M., Chernova, I., Iwai, Y., Long, A. J., Brown, J. A., Nunes, R., Greenfield, E. A., Bourque, K., Boussiotis, V. A., Carter, L. L., Carreno, B. M., Malenkovich, N., Nishimura, H., Okazaki, T., Honjo, T., Sharpe, A. H., & Freeman, G. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Kyoto University (JP)
- Corresponding author
- Freeman, Gordon J.
- ORCID
- Venue
- Nature Immunology
- Published
- 2001-03
- Volume
- 2
- Issue
- 3
- Pages
- 261-268
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2107752337
- Cited by
- 2,955
- References
- 2
- Citations by year
- 2026: 56 · 2025: 122 · 2024: 148 · 2023: 197 · 2022: 184 · 2021: 231 · 2020: 189 · 2019: 203 · 2018: 201 · 2017: 205 · 2016: 156 · 2015: 135 · 2014: 84 · 2013: 94 · 2012: 75
- FWCI
- 26.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI 38310, AI 39671, AI40614, R01AI040614, P01AI039671)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- PD-L2, PD-1, PD-L1, T cell activation, CD4+ T cells, T cell receptor signaling, CD28/B7 costimulation, cell cycle arrest, interferon-gamma, antigen-presenting cells, autoimmune tolerance, tumor immunology
- MeSH terms
- Amino Acid Sequence, Animals, Antigens, Surface, Blood Proteins, Cells, Cultured, Cricetinae, Humans, Ligands, Lymphocyte Activation, Membrane Glycoproteins, Mice, Inbred BALB C, Molecular Sequence Data, Peptides, Receptors, Antigen, T-Cell, T-Lymphocytes, Transfection, Antigens, CD, Cytokines, CHO Cells, Apoptosis, Sequence Homology, Amino Acid, CD28 Antigens, B7-1 Antigen, Jurkat Cells, Intercellular Signaling Peptides and Proteins, Apoptosis Regulatory Proteins, Mice, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Programmed Cell Death 1 Ligand 2 Protein
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