Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape
Open accessPublished version of a preprint
Abstract
Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here, we reveal extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4+ and CD8+ T cells in three distinct transplantable tumors. Dual anti–LAG-3/anti–PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, Lag3−/−Pdcd1−/− mice showed markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer. Cancer Res; 72(4); 917–27. ©2011 AACR.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Exhausted T cells may highly express multiple inhibitory receptors, including PD-1, 2B4, BTLA, CTLA-4, CD160, LAG-3, and Tim-3.
“Notably, exhausted T cells may highly express multiple “inhibitory” receptors, including PD-1, 2B4 (CD244), BTLA, CTLA-4, CD160, LAG-3 and Tim-3 [38,42,43,45].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [45]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J. C., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1003466 · Cited by 15,155 · see citing works
Cancer immunoediting: from immunosurveillance to tumor escape
Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J., & Schreiber, R. D. (2002) · Nature Immunology · doi:10.1038/ni1102-991 · Cited by 5,393 · see citing works
PD-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
Enhancement of Antitumor Immunity by CTLA-4 Blockade
Leach, D. R., Krummel, M. F., & Allison, J. P. (1996) · Science · doi:10.1126/science.271.5256.1734 · Cited by 3,955 · see citing works
Vignali, D. A. A., Collison, L. W., & Workman, C. J. (2008) · Nature Reviews Immunology · doi:10.1038/nri2343 · Cited by 3,463 · see citing works
Self-citationBrahmer, J. R., Drake, C. G., WOLLNER, I. S., Powderly, J. D., Picus, J., Sharfman, W. H., Stankevich, E., Pons, A., Salay, T. M., McMiller, T. L., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.26.7609 · Cited by 2,967 · see citing works
Self-citationCTLA-4 Control over Foxp3 <sup>+</sup> Regulatory T Cell Function
Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., & Sakaguchi, S. (2008) · Science · doi:10.1126/science.1160062 · Cited by 2,956 · see citing works
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
Nishimura, H., Nose, M., Hiai, H., Minato, N., & Honjo, T. (1999) · Immunity · doi:10.1016/s1074-7613(00)80089-8 · Cited by 2,749 · see citing works
The PD‐1 pathway in tolerance and autoimmunity
Francisco, L. M., Sage, P. T., & Sharpe, A. H. (2010) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00923.x · Cited by 2,300 · see citing works
Natural Innate and Adaptive Immunity to Cancer
Vesely, M. D., Kershaw, M. H., Schreiber, R. D., & Smyth, M. J. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-031210-101324 · Cited by 2,095 · see citing works
PD-L1 regulates the development, maintenance, and function of induced regulatory T cells
Francisco, L. M., Salinas, V. H., Brown, K. E., Vanguri, V. K., Freeman, G. J., Kuchroo, V. K., & Sharpe, A. H. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20090847 · Cited by 2,072 · see citing works
Blackburn, S. D., Shin, H., Haining, W. N., Zou, T., Workman, C. J., Polley, A., Betts, M. R., Freeman, G. J., Vignali, D. A. A., & Wherry, E. J. (2009) · Nature Immunology · doi:10.1038/ni.1679 · Cited by 2,062 · see citing works
Self-citationA New Approach to the Adoptive Immunotherapy of Cancer with Tumor-Infiltrating Lymphocytes
Rosenberg, S. A., Spiess, P. J., & Lafrenière, R. (1986) · Science · doi:10.1126/science.3489291 · Cited by 1,888 · see citing works
Autoimmune Dilated Cardiomyopathy in PD-1 Receptor-Deficient Mice
Nishimura, H., Okazaki, T., Tanaka, Y., Nakatani, K., Hara, M., Matsumori, A., Sasayama, S., Mizoguchi, A., Hiai, H., Minato, N., et al. (2001) · Science · doi:10.1126/science.291.5502.319 · Cited by 1,868 · see citing works
Role of LAG-3 in Regulatory T Cells
Huang, C.-T., Workman, C. J., Flies, D., Pan, X., Marson, A. L., Zhou, G., Hipkiss, E. L., Ravi, S., Kowalski, J., Levitsky, H. I., et al. (2004) · Immunity · doi:10.1016/j.immuni.2004.08.010 · Cited by 1,325 · see citing works
Self-citationIL-35-mediated induction of a potent regulatory T cell population
Collison, L. W., Chaturvedi, V., Henderson, A. L., Giacomin, P., Guy, C. S., Bankoti, J., Finkelstein, D., Forbes, K., Workman, C. J., Brown, S. A., et al. (2010) · Nature Immunology · doi:10.1038/ni.1952 · Cited by 870 · see citing works
Self-citationMatsuzaki, J., Gnjatic, S., Mhawech-Fauceglia, P., Beck, A., Miller, A., Tsuji, T., Eppolito, C., Qian, F., Lele, S., Shrikant, P., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003345107 · Cited by 859 · see citing works
Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR–induced stop signal
Fife, B. T., Pauken, K. E., Eagar, T. N., Kangas, T. O., Wu, J. Q., Tang, Q., Azuma, M., Krummel, M. F., & Bluestone, J. A. (2009) · Nature Immunology · doi:10.1038/ni.1790 · Cited by 759 · see citing works
The PD-1–PD-L pathway in immunological tolerance
Okazaki, T., & Honjo, T. (2006) · Trends in Immunology · doi:10.1016/j.it.2006.02.001 · Cited by 720 · see citing works
Liang, B., Workman, C., Lee, J., Chew, C., Dale, B. M., Colonna, L., Flores, M., Li, N., Schweighoffer, E., Greenberg, S., et al. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.9.5916 · Cited by 566 · see citing works
Self-citationConcomitant Tumor Immunity to a Poorly Immunogenic Melanoma Is Prevented by Regulatory T Cells
Turk, M. J., Guevara-Patino, J. A., Rizzuto, G. A., Engelhorn, M. E., & Houghton, A. N. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20041130 · Cited by 537 · see citing works
Grosso, J., Kelleher, C. C., Harris, T., Maris, C. H., Hipkiss, E. L., Marzo, A. D. D., Anders, R., Netto, G., Getnet, D., Bruno, T., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31184 · Cited by 531 · see citing works
Self-citationIwai, Y. (2004) · International Immunology · doi:10.1093/intimm/dxh194 · Cited by 527 · see citing works
Nishimura, H. (1998) · International Immunology · doi:10.1093/intimm/10.10.1563 · Cited by 500 · see citing works
Chambers, C. A., Sullivan, T. J., & Allison, J. P. (1997) · Immunity · doi:10.1016/s1074-7613(00)80406-9 · Cited by 406 · see citing works
Cutting Edge: Molecular Analysis of the Negative Regulatory Function of Lymphocyte Activation Gene-3
Workman, C. J., Dugger, K. J., & Vignali, D. A. A. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.10.5392 · Cited by 389 · see citing works
Self-citationGoldberg, M. V., & Drake, C. G. (2010) · Current topics in microbiology and immunology · doi:10.1007/82_2010_114 · Cited by 337 · see citing works
Self-citationNegative Regulation of T Cell Homeostasis by Lymphocyte Activation Gene-3 (CD223)
Workman, C. J., & Vignali, D. A. A. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.2.688 · Cited by 332 · see citing works
Self-citationPD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice
Okazaki, T., Okazaki, I., Wang, J., Sugiura, D., Nakaki, F., Yoshida, T., Kato, Y., Fagarasan, S., Muramatsu, M., Eto, T., et al. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20100466 · Cited by 328 · see citing works
The CD4‐related molecule, LAG‐3 (CD223), regulates the expansion of activated T cells
Workman, C. J., & Vignali, D. A. A. (2003) · European Journal of Immunology · doi:10.1002/eji.200323382 · Cited by 318 · see citing works
Self-citationLAG-3 Regulates Plasmacytoid Dendritic Cell Homeostasis
Workman, C. J., Wang, Y., Kasmi, K. C. E., Pardoll, D. M., Murray, P. J., Drake, C. G., & Vignali, D. A. A. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0800185 · Cited by 316 · see citing works
Self-citationAdler, A. J., Marsh, D. W., Yochum, G. S., Guzzo, J. L., Nigam, A., Nelson, W. G., & Pardoll, D. M. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.187.10.1555 · Cited by 294 · see citing works
Self-citationCostimulatory and coinhibitory receptors in anti‐tumor immunity
Driessens, G., Kline, J. P., & Gajewski, T. F. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2009.00771.x · Cited by 284 · see citing works
Functionally Distinct LAG-3 and PD-1 Subsets on Activated and Chronically Stimulated CD8 T Cells
Grosso, J. F., Goldberg, M. V., Getnet, D., Bruno, T. C., Yen, H., Pyle, K. J., Hipkiss, E. L., Vignali, D. A. A., Pardoll, D. M., & Drake, C. G. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0804211 · Cited by 272 · see citing works
Self-citationImproving T Cell Therapy for Cancer
Leen, A. M., Rooney, C. M., & Foster, A. E. (2006) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141527 · Cited by 238 · see citing works
Li, B., VanRoey, M. J., Wang, C., Chen, T.-H. T., Korman, A. J., & Jooss, K. U. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-1825 · Cited by 191 · see citing works
Self-citationRole of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells
Goldberg, M. V., Maris, C. H., Hipkiss, E. L., Flies, A. S., Zhen, L., Tuder, R. M., Grosso, J. F., Harris, T., Getnet, D., Whartenby, K. A., et al. (2007) · Blood · doi:10.1182/blood-2006-12-062422 · Cited by 187 · see citing works
Self-citationKocak, E., Lute, K. D., Chang, X., May, K. F., Exten, K. R., Zhang, H., Abdessalam, S. F., Lehman, A. M., Jarjoura, D. G., Zheng, P., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2128 · Cited by 177 · see citing works
Independent Modes of Natural Killing Distinguished in Mice Lacking Lag3
Miyazaki, T., Dierich, A., Benoist, C. O., & Mathis, D. J. (1996) · Science · doi:10.1126/science.272.5260.405 · Cited by 173 · see citing works
Ise, W., Kohyama, M., Nutsch, K., Lee, H. M., Suri, A., Unanue, E. R., Murphy, T. L., & MURPHY, K. M. M. (2009) · Nature Immunology · doi:10.1038/ni.1835 · Cited by 171 · see citing works
Cutting Edge: Accelerated Autoimmune Diabetes in the Absence of LAG-3
Bettini, M., Szymczak-Workman, A. L., Forbes, K., Castellaw, A. H., Selby, M., Pan, X., Drake, C. G., Korman, A. J., & Vignali, D. A. A. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100714 · Cited by 170 · see citing works
Self-citationAn essential role for Akt1 in dendritic cell function and tumor immunotherapy
Park, D., Lapteva, N., Seethammagari, M. R., Slawin, K. M., & Spencer, D. M. (2006) · Nature Biotechnology · doi:10.1038/nbt1262 · Cited by 115 · see citing works
Differential subcellular localization of the regulatory T‐cell protein LAG‐3 and the coreceptor CD4
Woo, S., Li, N., Bruno, T. C., Forbes, K., Brown, S. A., Workman, C. J., Drake, C. G., & Vignali, D. A. A. (2010) · European Journal of Immunology · doi:10.1002/eji.200939874 · Cited by 83 · see citing works
Self-citationInduction of Postsurgical Tumor Immunity and T-Cell Memory by a Poorly Immunogenic Tumor
Zhang, P., Côté, A. L., de Vries, V. C., Usherwood, E. J., & Turk, M. J. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1264 · Cited by 80 · see citing works
Niewiesk, S., Brinckmann, U., Bankamp, B., et al. (1993) · Journal of Virology · doi:10.1128/jvi.67.1.75-81.1993 · Cited by 67 · see citing works
Brenner, G. J., Cohen, N., & Moynihan, J. A. (1994) · Cellular Immunology · doi:10.1006/cimm.1994.1246 · Cited by 44 · see citing works
Noya, Ó. (1998) · Immunology Letters · doi:10.1016/s0165-2478(98)00055-8 · Cited by 41 · see citing works
The anti-tumor activity of anti-CTLA-4 is mediated through its induction of IFNγ
Paradis, T. J., Floyd, E., Burkwit, J., Cole, S. H., Brunson, B. L., Elliott, E. A., Gilman, S. C., & Gladue, R. P. (2001) · Cancer Immunology Immunotherapy · doi:10.1007/s002620100181 · Cited by 39 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
Self-citationThe future of immune checkpoint therapy
Sharma, P., & Allison, J. P. (2015) · Science · doi:10.1126/science.aaa8172 · Cited by 4,878 · see citing works
Immune 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
Self-citationInnate and adaptive immune cells in the tumor microenvironment
Gajewski, T. F., Schreiber, H., & Fu, Y.-X. (2013) · Nature Immunology · doi:10.1038/ni.2703 · Cited by 4,148 · see citing works
Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity
Spranger, S., Bao, R., & Gajewski, T. F. (2015) · Nature · doi:10.1038/nature14404 · Cited by 2,830 · see citing works
Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation
Anderson, A. C., Joller, N., & Kuchroo, V. K. (2016) · Immunity · doi:10.1016/j.immuni.2016.05.001 · Cited by 2,096 · see citing works
Immunotherapy in colorectal cancer: Rationale, challenges and potential
Ganesh, K., Stadler, Z. K., Cercek, A., Mendelsohn, R. B., Shia, J., Segal, N. H., & Diaz, L. A. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0126-x · Cited by 1,954 · see citing works
Mechanisms of resistance to immune checkpoint inhibitors
Jenkins, R. W., Barbie, D. A., & Flaherty, K. T. (2018) · British Journal of Cancer · doi:10.1038/bjc.2017.434 · Cited by 1,383 · see citing works
Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4
Qin, S., Xu, L., Yi, M., Yu, S., Wu, K., & Luo, S. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1091-2 · Cited by 1,145 · see citing works
VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors
Voron, T., Colussi, O., Marcheteau, E., Pernot, S., Nizard, M., Pointet, A.-L., Latreche, S., Bergaya, S., Benhamouda, N., Tanchot, C., et al. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20140559 · Cited by 1,179 · see citing works
Keren, L., Bosse, M., Marquez, D., Angoshtari, R., Jain, S., Varma, S., Yang, S.-R., Kurian, A., Van Valen, D., West, R., et al. (2018) · Cell · doi:10.1016/j.cell.2018.08.039 · Cited by 1,183 · see citing works
Gide, T. N., Quek, C., Menzies, A. M., Tasker, A. T., Shang, P., Holst, J., Madore, J., Lim, S. Y., Velickovic, R., Wongchenko, M., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.01.003 · Cited by 1,047 · see citing works
Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment
Ma, X., Bi, E., Lu, Y., Su, P., Huang, C., Liu, L., Wang, Q., Yang, M., Kalady, M. F., Qian, J., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.04.002 · Cited by 1,033 · see citing works
Combination cancer immunotherapies tailored to the tumour microenvironment
Smyth, M. J., Ngiow, S. F., Ribas, A., & Teng, M. W. L. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2015.209 · Cited by 944 · see citing works
Roh, W., Chen, P.-L., Reuben, A., Spencer, C. N., Prieto, P. A., Miller, J. P., Gopalakrishnan, V., Wang, F., Cooper, Z. A., Reddy, S. M., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aah3560 · Cited by 859 · see citing works
Scharping, N. E., Menk, A. V., Moreci, R. S., Whetstone, R. D., Dadey, R. E., Watkins, S. C., Ferris, R. L., & Delgoffe, G. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.07.009 · Cited by 848 · see citing works
T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment
Crespo, J., Sun, H., Welling, T. H., Tian, Z., & Zou, W. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.12.003 · Cited by 752 · see citing works
Chow, M. T., Ozga, A. J., Servis, R. L., Frederick, D. T., Lo, J. A., Fisher, D. E., Freeman, G. J., Boland, G. M., & Luster, A. D. (2019) · Immunity · doi:10.1016/j.immuni.2019.04.010 · Cited by 716 · see citing works
Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1-CD8+ Tumor-Infiltrating T Cells
Kurtulus, S., Madi, A., Escobar, G., Klapholz, M., Nyman, J., Christian, E., Pawlak, M., Dionne, D., Xia, J., Rozenblatt-Rosen, O., et al. (2019) · Immunity · doi:10.1016/j.immuni.2018.11.014 · Cited by 636 · see citing works
TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy
Molgora, M., Esaulova, E., Vermi, W., Hou, J., Chen, Y., Luo, J., Brioschi, S., Bugatti, M., Omodei, A. S., Ricci, B., et al. (2020) · Cell · doi:10.1016/j.cell.2020.07.013 · Cited by 656 · 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
<i>Ex Vivo</i> Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids
Jenkins, R. W., Aref, A. R., Lizotte, P. H., Ivanova, E., Stinson, S., Zhou, C. W., Bowden, M., Deng, J., Liu, H., Miao, D., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0833 · Cited by 594 · see citing works
Spranger, S., Koblish, H. K., Horton, B., Scherle, P. A., Newton, R., & Gajewski, T. F. (2014) · Journal for ImmunoTherapy of Cancer · doi:10.1186/2051-1426-2-3 · Cited by 552 · see citing works
Kouo, T., Huang, L., Pucsek, A. B., Cao, M., Solt, S., Armstrong, T., & Jaffee, E. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0150 · Cited by 531 · see citing works
Weber, J. S., Kudchadkar, R. R., Yu, B., Gallenstein, D., Horak, C. E., Inzunza, H. D., Zhao, X., Martinez, A. J., Wang, W., Gibney, G., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2013.51.4802 · Cited by 535 · see citing works
Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia
Scharping, N. E., Menk, A. V., Whetstone, R. D., Zeng, X., & Delgoffe, G. M. (2017) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-16-0103 · Cited by 520 · see citing works
Reversing T-cell Dysfunction and Exhaustion in Cancer
Zarour, H. M. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1849 · Cited by 462 · see citing works
Lymphocyte-activation gene 3 (LAG3): The next immune checkpoint receptor
Ruffo, E., Wu, R. C., Bruno, T. C., Workman, C. J., & Vignali, D. A. A. (2019) · Seminars in Immunology · doi:10.1016/j.smim.2019.101305 · Cited by 381 · see citing works
Self-citationBaessler, A., & Vignali, D. A. A. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-090222-110914 · Cited by 420 · see citing works
Self-citationEnvironmental Factors, Gut Microbiota, and Colorectal Cancer Prevention
Song, M., & Chan, A. T. (2019) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2018.07.012 · Cited by 355 · 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
T cells specific for α-myosin drive immunotherapy-related myocarditis
Axelrod, M. L., Meijers, W. C., Screever, E. M., Qin, J., Carroll, M. G., Sun, X., Tannous, E., Zhang, Y., Sugiura, A., Taylor, B. C., et al. (2022) · Nature · doi:10.1038/s41586-022-05432-3 · Cited by 367 · see citing works
Haist, M., Stege, H., Grabbe, S., & Bros, M. (2021) · Cancers · doi:10.3390/cancers13020210 · Cited by 295 · see citing works
TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer
Park, B. V., Freeman, Z. T., Ghasemzadeh, A., Chattergoon, M. A., Rutebemberwa, A., Steigner, J., Winter, M. E., Huynh, T. V., Sebald, S. M., Lee, S.-J., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1347 · Cited by 287 · see citing works
Self-citationMaruhashi, T., Okazaki, I.-M., Sugiura, D., Takahashi, S., Maeda, T. K., Shimizu, K., & Okazaki, T. (2018) · Nature Immunology · doi:10.1038/s41590-018-0217-9 · Cited by 275 · see citing works
VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy
Lines, J. L., Sempere, L. F., Broughton, T., Wang, L., & Noelle, R. (2014) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0072 · Cited by 236 · see citing works
Lussier, D. M., Johnson, J. L., Hingorani, P., & Blattman, J. N. (2015) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-015-0067-z · Cited by 206 · see citing works
Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors
Lidar, M., Giat, E., Garelick, D., Horowitz, Y., Amital, H., Steinberg-Silman, Y., Schachter, J., Shapira-Frommer, R., & Markel, G. (2018) · Autoimmunity Reviews · doi:10.1016/j.autrev.2018.01.003 · Cited by 180 · see citing works
Huo, J.-L., Wang, Y.-T., Fu, W.-J., Lu, N., & Liu, Z.-S. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.956090 · Cited by 176 · 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
Huang, M.-Y., Jiang, X.-M., Wang, B.-L., Sun, Y., & Lu, J.-J. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107694 · Cited by 136 · see citing works
Combination of Immunotherapy With Targeted Therapy: Theory and Practice in Metastatic Melanoma
Yu, C., Liu, X., Yang, J., Zhang, M., Jin, H., Ma, X., & Shi, H. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00990 · Cited by 126 · see citing works
Liu, Z., Ravindranathan, R., Li, J., Kalinski, P., Guo, Z. S., & Bartlett, D. L. (2016) · OncoImmunology · doi:10.1080/2162402x.2015.1091554 · Cited by 113 · see citing works
Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3
Grebinoski, S., Zhang, Q., Cillo, A. R., Manne, S., Xiao, H., Brunazzi, E. A., Tabib, T., Cardello, C., Lian, C. G., Murphy, G. F., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01210-5 · Cited by 107 · see citing works
Self-citationTrial watch: immune checkpoint blockers for cancer therapy
Vanpouille-Box, C., Lhuillier, C., Bezu, L., Aranda, F., Yamazaki, T., Kepp, O., Fucikova, J., Spisek, R., Demaria, S., Formenti, S. C., et al. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1373237 · Cited by 73 · see citing works
Gestermann, N., Saugy, D., Martignier, C., Tillé, L., Fuertes Marraco, S. A., Zettl, M., Tirapu, I., Speiser, D. E., & Verdeil, G. (2020) · OncoImmunology · doi:10.1080/2162402x.2020.1736792 · Cited by 69 · see citing works
Inhibitory receptor agonists: the future of autoimmune disease therapeutics?
Grebinoski, S., & Vignali, D. A. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.06.001 · Cited by 58 · see citing works
Self-citationQiu, M.-Z., Wang, C., Wu, Z., Zhao, Q., Zhao, Z., Huang, C.-Y., Wu, W., Yang, L.-Q., Zhou, Z.-W., Zheng, Y., et al. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01622-1 · Cited by 58 · see citing works
Immune 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
Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors
Roy, D., Gilmour, C., Patnaik, S., & Wang, L. L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1264327 · Cited by 53 · see citing works
Impact of Immunotherapy on CD4 T Cell Phenotypes and Function in Cancer
Saillard, M., Cenerenti, M., Romero, P., & Jandus, C. (2021) · Vaccines · doi:10.3390/vaccines9050454 · Cited by 23 · see citing works
- Authors
- Woo, S.-R., Turnis, M. E., Goldberg, M. V., Bankoti, J., Selby, M., Nirschl, C. J., Bettini, M. L., Gravano, D. M., Vogel, P., Liu, C. L., Tangsombatvisit, S., Grosso, J. F., Netto, G., Smeltzer, M. P., Chaux, A., Utz, P. J., Workman, C. J., Pardoll, D. M., Korman, A. J., Drake, C. G., & Vignali, D. A. A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Drake, Charles G.
- Vignali, Dario A.A.
- ORCID
- Venue
- Cancer Research
- Published
- 2012-02-14
- Volume
- 72
- Issue
- 4
- Pages
- 917-927
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3288154
- OpenAlex
- W2139591061
- Cited by
- 1,647
- References
- 50
- Citations by year
- 2026: 68 · 2025: 103 · 2024: 162 · 2023: 156 · 2022: 134 · 2021: 187 · 2020: 134 · 2019: 128 · 2018: 119 · 2017: 116 · 2016: 117 · 2015: 112 · 2014: 48 · 2013: 47 · 2012: 14
- FWCI
- 17.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service (HHSN-268201999934C)
- Canadian Institutes of Health Research (20R-92141)
- National Cancer Institute (P50 CA58236-15, CA21765, P50CA058236, R01CA127153, P30CA021765)
- National Institute of Allergy and Infectious Diseases (F32AI080086, R01AI039480, R01 AI39480, T32AI007247)
- 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 › Immunotherapy and Immune Responses
- Keywords
- LAG-3, PD-1, inhibitory receptors, tumor immune evasion, T cell function, CTLA-4, tumor-infiltrating T cells, autoimmune tolerance, self-tolerance, transplantable tumors
- MeSH terms
- Lymphocyte Activation Gene 3 Protein, Animals, Antibodies, Drug Synergism, Immune Tolerance, Mice, Inbred C57BL, Neoplasm Transplantation, Neoplasms, Experimental, CD4-Positive T-Lymphocytes, Antigens, CD, Tumor Escape, Cell Line, Tumor, Mice, Programmed Cell Death 1 Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
