Photo of Gordon J. Freeman,  PhD

Gordon J. Freeman, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-4585
Fax: (617) 632-5167


gordon_freeman@dfci.harvard.edu

Gordon J. Freeman, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

My laboratory studies the role of costimulatory signals in the development of an immune response. T cell activation requires two signals. Specificity is provided by TCR recognition of peptide-MHC complexes but a second, costimulatory signal is required for full T cell activation. The B7 gene family, comprised of B7-1 and B7-2, provide the critical costimulatory signal for full T cell activation, clonal expansion, and development of effector function through their interaction with CD28 on T cells. After T cell activation, the interaction of B7-1 and B7-2 with the higher affinity ligand, CTLA4, expressed on activated T cells, leads to down-regulation of T cell activation. Stimulation of the TCR alone leads to T cell clonal anergy thus blockade of B7-1 and B7-2 can be used to establish antigen-specific tolerance for transplantation or the alleviation of autoimmunity. Conversely, expression of B7-1 and B7-2 can stimulate an immune response and the introduction of B7-1 or B7-2 into tumors can stimulate an anti-tumor response leading to tumor rejection and anti-tumor immunity. Recently, we have cloned two novel members of the B7 gene family. These new B7s bind to receptors expressed on activated T cells and further regulate the development of an immune response. We are currently focusing on the function of these novel B7 genes and their interactions with the B7/CD28-CTLA4 pathway.

Publications

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  • Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, Connelly CF, Sun HH, Daadi SE, Freeman GJ, Armand P, Chapuy B, de Jong D, Hoppe RT, Neuberg DS, Rodig SJ, Shipp MA. PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. J Clin Oncol 2016. PubMed
  • Xu J, Sun HH, Fletcher CD, Hornick JL, Morgan EA, Freeman GJ, Hodi FS, Pinkus GS, Rodig SJ. Expression of Programmed Cell Death 1 Ligands (PD-L1 and PD-L2) in Histiocytic and Dendritic Cell Disorders. Am J Surg Pathol 2016; 40:443-53. PubMed
  • Howitt BE, Sun HH, Roemer MG, Kelley A, Chapuy B, Aviki E, Pak C, Connelly C, Gjini E, Shi Y, Lee L, Viswanathan A, Horowitz N, Neuberg D, Crum CP, Lindeman NL, Kuo F, Ligon AH, Freeman GJ, Hodi FS, Shipp MA, Rodig SJ. Genetic Basis for PD-L1 Expression in Squamous Cell Carcinomas of the Cervix and Vulva. JAMA Oncol 2016; 2:518-22. PubMed
  • Llibre A, López-Macías C, Marafioti T, Mehta H, Partridge A, Kanzig C, Rivellese F, Galson JD, Walker LJ, Milne P, Phillips RE, Kelly DF, Freeman GJ, El Shikh ME, Klenerman P, Willberg CB. LLT1 and CD161 Expression in Human Germinal Centers Promotes B Cell Activation and CXCR4 Downregulation. J Immunol 2016; 196:2085-94. PubMed
  • Koyama S, Akbay EA, Li YY, Aref AR, Skoulidis F, Herter-Sprie GS, Buczkowski KA, Liu Y, Awad MM, Denning WL, Diao L, Wang J, Parra-Cuentas ER, Wistuba II, Soucheray M, Thai T, Asahina H, Kitajima S, Altabef A, Cavanaugh JD, Rhee K, Gao P, Zhang H, Fecci PE, Shimamura T, Hellmann MD, Heymach JV, Hodi FS, Freeman GJ, Barbie DA, Dranoff G, Hammerman PS, Wong KK. STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment. Cancer Res 2016; 76:999-1008. PubMed
  • Concha-Benavente F, Srivastava RM, Trivedi S, Lei Y, Chandran U, Seethala RR, Freeman GJ, Ferris RL. Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer. Cancer Res 2016; 76:1031-43. PubMed
  • Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH. Coinhibitory Pathways in Immunotherapy for Cancer. Annu Rev Immunol 2016. PubMed
  • Chapuy B, Roemer MG, Stewart C, Tan Y, Abo RP, Zhang L, Dunford AJ, Meredith DM, Thorner AR, Jordanova ES, Liu G, Feuerhake F, Ducar MD, Illerhaus G, Gusenleitner D, Linden EA, Sun HH, Homer H, Aono M, Pinkus GS, Ligon AH, Ligon KL, Ferry JA, Freeman GJ, van Hummelen P, Golub TR, Getz G, Rodig SJ, de Jong D, Monti S, Shipp MA. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 2016; 127:869-81. PubMed
  • Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, Yamazaki T, Poirier-Colame V, Newton A, Redouane Y, Lin YJ, Wojtkiewicz G, Iwamoto Y, Mino-Kenudson M, Huynh TG, Hynes RO, Freeman GJ, Kroemer G, Zitvogel L, Weissleder R, Pittet MJ. Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity 2016; 44:343-54. PubMed
  • Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, Gandhi L, Redig AJ, Rodig SJ, Asahina H, Jones RE, Kulkarni MM, Kuraguchi M, Palakurthi S, Fecci PE, Johnson BE, Janne PA, Engelman JA, Gangadharan SP, Costa DB, Freeman GJ, Bueno R, Hodi FS, Dranoff G, Wong KK, Hammerman PS. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun 2016; 7:10501. PubMed
  • Mahoney KM, Sun H, Liao X, Hua P, Callea M, Greenfield EA, Hodi FS, Sharpe AH, Signoretti S, Rodig SJ, Freeman GJ. PD-L1 Antibodies to Its Cytoplasmic Domain Most Clearly Delineate Cell Membranes in Immunohistochemical Staining of Tumor Cells. Cancer Immunol Res 2015; 3:1308-15. PubMed
  • Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, Jones KL, Conway AS, Liao X, Zhou J, Wen PY, Van Den Abbeele AD, Hodi FS, Qin L, Kohl NE, Sharpe AH, Dranoff G, Freeman GJ. Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model. Cancer Immunol Res 2015. PubMed
  • Calles A, Liao X, Sholl LM, Rodig SJ, Freeman GJ, Butaney M, Lydon C, Dahlberg SE, Hodi FS, Oxnard GR, Jackman DM, Jänne PA. Expression of PD-1 and its ligands, PD-L1 and PD-L2, in smokers and never smokers with KRAS mutant lung cancer. J Thorac Oncol 2015. PubMed
  • Callea M, Albiges L, Gupta M, Cheng SC, Genega EM, Fay AP, Song J, Carvo I, Bhatt RS, Atkins MB, Hodi FS, Choueiri TK, McDermott DF, Freeman GJ, Signoretti S. Differential Expression of PD-L1 between Primary and Metastatic Sites in Clear-Cell Renal Cell Carcinoma. Cancer Immunol Res 2015. PubMed
  • Derks S, Nason KS, Liao X, Stachler MD, Liu KX, Liu JB, Sicinska E, Goldberg MS, Freeman GJ, Rodig SJ, Davison JM, Bass AJ. Epithelial PD-L2 Expression Marks Barrett's Esophagus and Esophageal Adenocarcinoma. Cancer Immunol Res 2015. PubMed
  • Mima K, Nishihara R, Nowak JA, Kim SA, Song M, Inamura K, Sukawa Y, Masuda A, Yang J, Dou R, Nosho K, Baba H, Giovannucci EL, Bowden M, Loda M, Giannakis M, Bass AJ, Dranoff G, Freeman GJ, Chan AT, Fuchs CS, Qian ZR, Ogino S. MicroRNA MIR21 and T Cells in Colorectal Cancer. Cancer Immunol Res 2015. PubMed
  • Paterson AM, Lovitch SB, Sage PT, Juneja VR, Lee Y, Trombley JD, Arancibia-Cárcamo CV, Sobel RA, Rudensky AY, Kuchroo VK, Freeman GJ, Sharpe AH. Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity. J Exp Med 2015; 212:1603-21. PubMed
  • Mima K, Nishihara R, Qian ZR, Cao Y, Sukawa Y, Nowak JA, Yang J, Dou R, Masugi Y, Song M, Kostic AD, Giannakis M, Bullman S, Milner DA, Baba H, Giovannucci EL, Garraway LA, Freeman GJ, Dranoff G, Garrett WS, Huttenhower C, Meyerson M, Meyerhardt JA, Chan AT, Fuchs CS, Ogino S. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut 2015. PubMed
  • Mima K, Sukawa Y, Nishihara R, Qian ZR, Yamauchi M, Inamura K, Kim SA, Masuda A, Nowak JA, Nosho K, Kostic AD, Giannakis M, Watanabe H, Bullman S, Milner DA, Harris CC, Giovannucci E, Garraway LA, Freeman GJ, Dranoff G, Chan AT, Garrett WS, Huttenhower C, Fuchs CS, Ogino S. Fusobacterium nucleatum and T Cells in Colorectal Carcinoma. JAMA Oncol 2015. PubMed
  • Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 2015; 14:561-84. PubMed
  • Goldberg JM, Fisher DE, Demetri GD, Neuberg D, Allsop SA, Fonseca C, Nakazaki Y, Nemer D, Raut CP, George S, Morgan JA, Wagner AJ, Freeman GJ, Ritz J, Lezcano C, Mihm M, Canning C, Hodi FS, Dranoff G. Biologic Activity of Autologous, Granulocyte-Macrophage Colony-Stimulating Factor Secreting Alveolar Soft-Part Sarcoma and Clear Cell Sarcoma Vaccines. Clin Cancer Res 2015. PubMed
  • Sage PT, Tan CL, Freeman GJ, Haigis M, Sharpe AH. Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging. Cell Rep 2015; 12:163-71. PubMed
  • Bellucci R, Martin A, Bommarito D, Wang K, Hansen SH, Freeman GJ, Ritz J. Interferon-γ-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression. Oncoimmunology 2015; 4:e1008824. PubMed
  • Veenstra RG, Flynn R, Kreymborg K, McDonald-Hyman C, Saha A, Taylor PA, Osborn MJ, Panoskaltsis-Mortari A, Schmitt-Graeff A, Lieberknect E, Murphy WJ, Serody JS, Munn DH, Freeman GJ, Allison JP, Mak TW, van den Brink M, Zeiser R, Blazar BR. B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality. Blood 2015. PubMed
  • Xiao Y, Freeman GJ. A New B7:CD28 Family Checkpoint Target for Cancer Immunotherapy: HHLA2. Clin Cancer Res 2015; 21:2201-3. PubMed
  • Bellmunt J, Mullane SA, Werner L, Fay AP, Callea M, Leow JJ, Taplin ME, Choueiri TK, Hodi FS, Freeman GJ, Signoretti S. Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Ann Oncol 2015; 26:812-7. PubMed
  • Mahoney KM, Freeman GJ, McDermott DF. The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma. Clin Ther 2015. PubMed
  • Balan M, Mier y Teran E, Waaga-Gasser AM, Gasser M, Choueiri TK, Freeman G, Pal S. Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression. J Biol Chem 2015; 290:8110-20. PubMed
  • Maazi H, Patel N, Sankaranarayanan I, Suzuki Y, Rigas D, Soroosh P, Freeman GJ, Sharpe AH, Akbari O. ICOS:ICOS-ligand interaction is required for type 2 innate lymphoid cell function, homeostasis, and induction of airway hyperreactivity. Immunity 2015; 42:538-51. PubMed
  • Du Z, Abedalthagafi M, Aizer AA, McHenry AR, Sun HH, Bray MA, Viramontes O, Machaidze R, Brastianos PK, Reardon DA, Dunn IF, Freeman GJ, Ligon KL, Carpenter AE, Alexander BM, Agar NY, Rodig SJ, Bradshaw EM, Santagata S. Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma. 2015; 6:4704-16. PubMed
  • Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015; 372:311-9. PubMed
  • Buchan SL, Manzo T, Flutter B, Rogel A, Edwards N, Zhang L, Sivakumaran S, Ghorashian S, Carpenter B, Bennett CL, Freeman GJ, Sykes M, Croft M, Al-Shamkhani A, Chakraverty R. OX40- and CD27-mediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence. J Immunol 2014; 194:125-33. PubMed
  • Fay AP, Signoretti S, Callea M, Telό GH, McKay RR, Song J, Carvo I, Lampron ME, Kaymakcalan MD, Poli-de-Figueiredo CE, Bellmunt J, Hodi FS, Freeman GJ, Elfiky A, Choueiri TK. Programmed death ligand-1 expression in adrenocortical carcinoma: an exploratory biomarker study. J Immunother Cancer 2015; 3:3. PubMed
  • Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, Karoly ED, Freeman GJ, Petkova V, Seth P, Li L, Boussiotis VA. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 2015; 6:6692. PubMed
  • Xiao Y, Freeman GJ. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. 2015; 5:16-8. PubMed
  • Shi M, Roemer MG, Chapuy B, Liao X, Sun H, Pinkus GS, Shipp MA, Freeman GJ, Rodig SJ. Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain. Am J Surg Pathol 2014. PubMed
  • Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, Ivanova Y, Hundal J, Arthur CD, Krebber WJ, Mulder GE, Toebes M, Vesely MD, Lam SS, Korman AJ, Allison JP, Freeman GJ, Sharpe AH, Pearce EL, Schumacher TN, Aebersold R, Rammensee HG, Melief CJ, Mardis ER, Gillanders WE, Artyomov MN, Schreiber RD. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014; 515:577-81. PubMed
  • Fergusson JR, Smith KE, Fleming VM, Rajoriya N, Newell EW, Simmons R, Marchi E, Björkander S, Kang YH, Swadling L, Kurioka A, Sahgal N, Lockstone H, Baban D, Freeman GJ, Sverremark-Ekström E, Davis MM, Davenport MP, Venturi V, Ussher JE, Willberg CB, Klenerman P. CD161 defines a transcriptional and functional phenotype across distinct human T cell lineages. Cell Rep 2014; 9:1075-88. PubMed
  • Reardon DA, Freeman G, Wu C, Chiocca EA, Wucherpfennig KW, Wen PY, Fritsch EF, Curry WT, Sampson JH, Dranoff G. Immunotherapy advances for glioblastoma. 2014; 16:1441-58. PubMed
  • Penaloza-MacMaster P, Kamphorst AO, Wieland A, Araki K, Iyer SS, West EE, O'Mara L, Yang S, Konieczny BT, Sharpe AH, Freeman GJ, Rudensky AY, Ahmed R. Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med 2014; 211:1905-18. PubMed
  • Cooper ZA, Juneja VR, Sage PT, Frederick DT, Piris A, Mitra D, Lo JA, Hodi FS, Freeman GJ, Bosenberg MW, McMahon M, Flaherty KT, Fisher DE, Sharpe AH, Wargo JA. Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade. Cancer Immunol Res 2014. PubMed
  • Flynn R, Du J, Veenstra RG, Reichenbach DK, Panoskaltsis-Mortari A, Taylor PA, Freeman GJ, Serody JS, Murphy WJ, Munn DH, Sarantopoulos S, Luznik L, Maillard I, Koreth J, Cutler C, Soiffer RJ, Antin JH, Ritz J, Dubovsky JA, Byrd JC, MacDonald KP, Hill GR, Blazar BR. Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood 2014. PubMed
  • Xu C, Fillmore CM, Koyama S, Wu H, Zhao Y, Chen Z, Herter-Sprie GS, Akbay EA, Tchaicha JH, Altabef A, Reibel JB, Walton Z, Ji H, Watanabe H, Jänne PA, Castrillon DH, Rustgi AK, Bass AJ, Freeman GJ, Padera RF, Dranoff G, Hammerman PS, Kim CF, Wong KK. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 2014; 25:590-604. PubMed
  • Xiao Y, Yu S, Zhu B, Bedoret D, Bu X, Francisco LM, Hua P, Duke-Cohan JS, Umetsu DT, Sharpe AH, DeKruyff RH, Freeman GJ. RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med 2014. PubMed
  • Kroy DC, Ciuffreda D, Cooperrider JH, Tomlinson M, Hauck GD, Aneja J, Berger C, Wolski D, Carrington M, Wherry EJ, Chung RT, Tanabe KK, Elias N, Freeman GJ, de Kruyff RH, Misdraji J, Kim AY, Lauer GM. Liver environment and HCV replication affect human T-cell phenotype and expression of inhibitory receptors. Gastroenterology 2014; 146:550-61. PubMed
  • Duraiswamy J, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors--response. Cancer Res 2014; 74:633-4; discussion 635. PubMed
  • Mott KR, Allen SJ, Zandian M, Akbari O, Hamrah P, Maazi H, Wechsler SL, Sharpe AH, Freeman GJ, Ghiasi H. Inclusion of CD80 in HSV targets the recombinant virus to PD-L1 on DCs and allows productive infection and robust immune responses. PLoS ONE 2014; 9:e87617. PubMed
  • Duraiswamy J, Freeman GJ, Coukos G. Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res 2013; 73:6900-12. PubMed
  • Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, Mikse OR, Cherniack AD, Beauchamp EM, Pugh TJ, Wilkerson MD, Fecci PE, Butaney M, Reibel JB, Soucheray M, Cohoon TJ, Janne PA, Meyerson M, Hayes DN, Shapiro GI, Shimamura T, Sholl LM, Rodig SJ, Freeman GJ, Hammerman PS, Dranoff G, Wong KK. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. 2013. PubMed
  • Saha A, Aoyama K, Taylor PA, Koehn BH, Veenstra RG, Panoskaltsis-Mortari A, Munn DH, Murphy WJ, Azuma M, Yagita H, Fife BT, Sayegh MH, Najafian N, Socie G, Ahmed R, Freeman GJ, Sharpe AH, Blazar BR. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood 2013; 122:3062-73. PubMed
  • Fuller MJ, Callendret B, Zhu B, Freeman GJ, Hasselschwert DL, Satterfield W, Sharpe AH, Dustin LB, Rice CM, Grakoui A, Ahmed R, Walker CM. Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1). Proc Natl Acad Sci U S A 2013; 110:15001-6. PubMed
  • Kim HY, Chang YJ, Chuang YT, Lee HH, Kasahara DI, Martin T, Hsu JT, Savage PB, Shore SA, Freeman GJ, Dekruyff RH, Umetsu DT. T-cell immunoglobulin and mucin domain 1 deficiency eliminates airway hyperreactivity triggered by the recognition of airway cell death. J Allergy Clin Immunol 2013; 132:414-25.e6. PubMed
  • Wei F, Zhong S, Ma Z, Kong H, Medvec A, Ahmed R, Freeman GJ, Krogsgaard M, Riley JL. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc Natl Acad Sci U S A 2013. PubMed
  • Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MG, Xu ML, Yu H, Fletcher CD, Freeman GJ, Shipp MA, Rodig SJ. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 2013; 19:3462-73. PubMed
  • Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res 2013; 73:3591-603. PubMed
  • Reardon DA, Wucherpfennig KW, Freeman G, Wu CJ, Chiocca EA, Wen PY, Curry WT, Mitchell DA, Fecci PE, Sampson JH, Dranoff G. An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma. 2013; 12:597-615. PubMed
  • Naito M, Hainz U, Burkhardt UE, Fu B, Ahove D, Stevenson KE, Rajasagi M, Zhu B, Alonso A, Witten E, Matsuoka K, Neuberg D, Duke-Cohan JS, Wu CJ, Freeman GJ. CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells. Cancer Immunol Immunother 2013. PubMed
  • D'Addio F, Ueno T, Clarkson M, Zhu B, Vergani A, Freeman GJ, Sayegh MH, Ansari MJ, Fiorina P, Habicht A. CD160Ig fusion protein targets a novel costimulatory pathway and prolongs allograft survival. PLoS ONE 2013; 8:e60391. PubMed
  • Chou CK, Schietinger A, Liggitt HD, Tan X, Funk S, Freeman GJ, Ratliff TL, Greenberg NM, Greenberg PD. Cell-intrinsic abrogation of TGF-β signaling delays but does not prevent dysfunction of self/tumor-specific CD8 T cells in a murine model of autochthonous prostate cancer. J Immunol 2012; 189:3936-46. PubMed
  • Bu DX, Tarrio M, Maganto-Garcia E, Stavrakis G, Tajima G, Lederer J, Jarolim P, Freeman GJ, Sharpe AH, Lichtman AH. Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation. Arterioscler Thromb Vasc Biol 2011. PubMed
  • Allen SJ, Hamrah P, Gate D, Mott KR, Mantopoulos D, Zheng L, Town T, Jones C, von Andrian UH, Freeman GJ, Sharpe AH, BenMohamed L, Ahmed R, Wechsler SL, Ghiasi H. The role of LAT in increased CD8+ T cell exhaustion in trigeminal ganglia of mice latently infected with herpes simplex virus 1. J Virol 2011. PubMed
  • Albacker LA, Karisola P, Chang YJ, Umetsu SE, Zhou M, Akbari O, Kobayashi N, Baumgarth N, Freeman GJ, Umetsu DT, DeKruyff RH. TIM-4, a receptor for phosphatidylserine, controls adaptive immunity by regulating the removal of antigen-specific T cells. J Immunol 2010; 185:6839-49. PubMed
  • Flutter B, Edwards N, Fallah-Arani F, Henderson S, Chai JG, Sivakumaran S, Ghorashian S, Bennett CL, Freeman GJ, Sykes M, Chakraverty R. Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation. J Clin Invest 2010; 120:3855-68. PubMed
  • Dorfman DM, Hornick JL, Shahsafaei A, Freeman GJ. The phosphatidylserine receptors, T cell immunoglobulin mucin proteins 3 and 4, are markers of histiocytic sarcoma and other histiocytic and dendritic cell neoplasms. Hum Pathol 2010; 41:1486-94. PubMed
  • Peña-Cruz V, McDonough SM, Diaz-Griffero F, Crum CP, Carrasco RD, Freeman GJ. PD-1 on Immature and PD-1 Ligands on Migratory Human Langerhans Cells Regulate Antigen-Presenting Cell Activity. J Invest Dermatol 2010; 130:2222-30. PubMed
  • El Annan J, Goyal S, Zhang Q, Freeman GJ, Sharpe AH, Dana R. Regulation of T-cell chemotaxis by programmed death-ligand 1 (PD-L1) in dry eye-associated corneal inflammation. Invest Ophthalmol Vis Sci 2010; 51:3418-23. PubMed
  • Brown KE, Freeman GJ, Wherry EJ, Sharpe AH. Role of PD-1 in regulating acute infections. Curr Opin Immunol 2010; 22:397-401. PubMed
  • Freeman GJ, Casasnovas JM, Umetsu DT, DeKruyff RH. TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev 2010; 235:172-89. PubMed
  • DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, Karisola P, Pichavant M, Kaplan GG, Umetsu DT, Freeman GJ, Casasnovas JM. T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol 2010; 184:1918-30. PubMed
  • Blackburn SD, Crawford A, Shin H, Polley A, Freeman GJ, Wherry EJ. Tissue-specific differences in PD-1 and PD-L1 expression during chronic viral infection: implications for CD8 T-cell exhaustion. J Virol 2010; 84:2078-89. PubMed
  • Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 2009; 206:3015-29. PubMed
  • Currie AJ, Prosser A, McDonnell A, Cleaver AL, Robinson BW, Freeman GJ, van der Most RG. Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation. J Immunol 2009; 183:7898-908. PubMed
  • Chen L,Sham CW,Chan AM,Francisco LM,Wu Y,Mareninov S,Sharpe AH,Freeman G,Yang XJ,Braun J,Gordon LK. Role of the immune modulator programmed cell death-1 during development and apoptosis of mouse retinal ganglion cells. Invest Ophthalmol Vis Sci 2009; 50:4941-8. PubMed
  • Sauce D, Larsen M, Abbott RJ, Hislop AD, Leese AM, Khan N, Papagno L, Freeman GJ, Rickinson AB. Upregulation of interleukin 7 receptor alpha and programmed death 1 marks an epitope-specific CD8+ T-cell response that disappears following primary Epstein-Barr virus infection. J Virol 2009; 83:9068-78. PubMed
  • Brainard DM,Seung E,Frahm N,Cariappa A,Bailey CC,Hart WK,Shin HS,Brooks SF,Knight HL,Eichbaum Q,Yang YG,Sykes M,Walker BD,Freeman GJ,Pillai S,Westmoreland SV,Brander C,Luster AD,Tager AM. Induction of robust cellular and humoral virus-specific adaptive immune responses in HIV-infected humanized BLT mice. J Virol 2009; 83:7305-21. PubMed
  • Yuan X, Ansari MJ, D'Addio F, Paez-Cortez J, Schmitt I, Donnarumma M, Boenisch O, Zhao X, Popoola J, Clarkson MR, Yagita H, Akiba H, Freeman GJ, Iacomini J, Turka LA, Glimcher LH, Sayegh MH. Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells. Proc Natl Acad Sci U S A 2009; 106:10734-9. PubMed
  • Cai G,Freeman GJ. The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunol Rev 2009; 229:244-58. PubMed
  • Velu V,Titanji K,Zhu B,Husain S,Pladevega A,Lai L,Vanderford TH,Chennareddi L,Silvestri G,Freeman GJ,Ahmed R,Amara RR. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 2008; 458:206-10. PubMed
  • Reynoso ED,Elpek KG,Francisco L,Bronson R,Bellemare-Pelletier A,Sharpe AH,Freeman GJ,Turley SJ. Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade. J Immunol 2009; 182:2102-12. PubMed
  • Nakamoto N,Cho H,Shaked A,Olthoff K,Valiga ME,Kaminski M,Gostick E,Price DA,Freeman GJ,Wherry EJ,Chang KM. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog 2009; 5:e1000313. PubMed
  • Chen L,Pai V,Levinson R,Sharpe AH,Freeman GJ,Braun J,Gordon LK. Constitutive neuronal expression of the immune regulator, programmed death 1 (PD-1), identified during experimental autoimmune uveitis. Ocul Immunol Inflamm 2009; 17:47-55. PubMed
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