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. Moreover, therapy-induced antibodies to MICA overcome immune suppression and enhancing cytotoxic T cell responses.
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.
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Papers & Publications:
1. Jinushi M, Hodi FS, Dranoff G. Therapy-induced antibodies to MHC class I-related protein A antagonize immune suppression and stimulate anti-tumor cytotoxicity. Proc. Natl. Acad. Sci. U.S.A. 2006;103:9190-9195.
2. Hodi FS, Dranoff G. Combinatorial cancer immunotherapy. Adv. Immunol. 2006;90:341-368.
3. Jinushi M, Nakazaki Y, Dougan M, Carrasco DR, Mihm M, Dranoff G. MFG-E8 mediated uptake of apoptotic cells by APCs links the pro- and anti-inflammatory activities of GM-CSF. J. Clin. Invest. 2007;117:1902-1913.
4. Jinushi M and Dranoff G. Triggering tumor immunity through targeting angiogenesis. Clin. Cancer Res. 2007;13:3762-3764.
5. Enzler T, Gillessen S, Dougan M, Allison JP, Neuberg D, Oble DA, Mihm M, Dranoff G. Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of b-cells. Blood 2007;110:954-961. |
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