Glenn Dranoff
Department of Medicine
Dana-Farber Cancer Institute
Dana Building, Room 520C
44 Binney Street
Boston, MA 02115
Tel: 617-632-5051
Fax: 617-632-5167
e-mail:glenn_dranoff@dfci.harvard.edu
4 Postdoctoral Fellows, 3 Graduate Students
Our laboratory studies the molecular and cellular mechanisms underlying the generation of anti-tumor immunity. We have demonstrated that vaccination with irradiated tumor cells engineered to secrete GM-CSF stimulates potent, specific, and long-lasting anti-tumor immunity in multiple murine tumor model systems. Vaccination enhances the function of CD11b+ dendritic cells; CD1d-restricted invariant NKT cells, CD4+ and CD8+ T cells, and antibodies mediate tumor rejection. In a variety of human cancers, this immunization strategy elicits dense CD4+ and CD8+ T lymphocyte and plasma cell infiltrates in distant metastases, resulting in extensive tumor necrosis. CTLA-4 antibody blockade further increases anti-tumor memory responses. To identify the target antigens underlying tumor destruction, we used sera and T cells from vaccinated patients to screen tumor cell-derived cDNA expression libraries. Several rejection antigens with critical roles in transformation have been characterized thus far, including a novel inhibitor of apoptosis protein, angiogenic cytokines, and components of the NKG2D pathway. Efforts to characterize the therapy-induced antibodies with functional activity are underway.
We have also generated mice lacking GM-CSF, interleukin-3, and interferon-gamma through gene targeting techniques. These animals spontaneously develop at high frequency diverse hematologic and solid neoplasms within a background of persistent infection and inflammation. Analyses of these mice have established that milk fat globule EGF protein 8 mediated uptake of apoptotic cells by antigen presenting cells plays a key role in the pro- and anti-inflammatory activities of GM-CSF. Therapeutic strategies modulating MFG-E8 function are under investigation.
References:
Fonseca C, Soiffer R, Ho V, Vanneman M, Jinushi M, Ritz J, Neuberg D, Stone R, DeAngelo D, Dranoff G. Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction. Blood 2009;113:1681-1688.
Jinushi M, Sato M, Kanamoto A, Itoh A, Nagai S, Koyasu S, Dranoff G, Tahara H. Milk fat globule EGF-8 blockade triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms. J. Exp. Med. 2009;206:1317-1326.
Dougan M and Dranoff G. Immune therapy for cancer. Ann. Rev. Immunol. 2009, 27:83-117.
Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, MacRae S, Nelson M, Canning C, Lowy I, Korman A, Lautz D, Russell S, Jaklitsch, Ramaiya N, Chen TC, Neuberg D, Allison JP, Mihm MC, and Dranoff G. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc. Natl. Acad. Sci. U.S.A. 2008;105:3005-3010.
Immunology webpage updated 1/15/2010