Extracellular heat shock proteins (HSP) have been shown to have a profound effect on tumor immunity. We have prepared a highly effective cancer vaccine by extracting Hsp70/Hsp90 complexes from the fusion of tumor cells and dendritic cells (Hsp70.PC-F).
We aim i n this proposal to examine the properties of the vaccine and optimize its use either solo or combined with ionizing radiation.
We aim first to understand the role of the receptor SRECI in dendritic cells (DC) in binding to Hsp70.PC-F and subsequent uptake and presentation of antigens to T lymphocytes.
We aim to determine how SRECI can orchestrate antigen cross presentation, innate immune stimulation and cell regulation in DC. Next, in the translational studies in Aim 2 we will examine the role of Hsp70.PC-F in treatment of spontaneous mammary carcinoma in mice.
We aim to determine treatment effectiveness and the degree to which vaccines can be used in combination with adjuvants such as TLR3 and TLR9 agonists as well as inhibitors of co-repressing molecule CTLA4. We will further determine whether vaccine design can be manipulated to give selective destruction of tumor initiating cells and radiation resistant cells that accumulate in fractionated radiation therapy.

Public Health Relevance

Immunotherapy and radiation therapy, when combined, may be highly effective in cancer therapy, as radiation can kill the majority of cells in the tumor whie immunotherapy is capable of targeting small colonies of disseminated cells (metastases). We have devised a novel vaccine with unique properties based on extracting heat shock proteins from tumors and injecting them into tumor bearing mice. We will determine the effectiveness of the vaccine in killing mouse mammary tumor cells alone or in combination with biological adjuvants and ionizing radiation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA119045-07
Application #
8537837
Study Section
Special Emphasis Panel (ZRG1-OTC-C (04))
Program Officer
Wong, Rosemary S
Project Start
2005-12-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
7
Fiscal Year
2013
Total Cost
$291,982
Indirect Cost
$60,248
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Calderwood, Stuart K (2016) Creative damage unleashes transcription. Cell Cycle 15:1021-2
Calderwood, Stuart K; Gong, Jianlin; Murshid, Ayesha (2016) Extracellular HSPs: The Complicated Roles of Extracellular HSPs in Immunity. Front Immunol 7:159
Calderwood, Stuart K; Gong, Jianlin (2016) Heat Shock Proteins Promote Cancer: It's a Protection Racket. Trends Biochem Sci 41:311-23
Calderwood, Stuart K; Neckers, Len (2016) Hsp90 in Cancer: Transcriptional Roles in the Nucleus. Adv Cancer Res 129:89-106
Murshid, Ayesha; Gong, Jianlin; Prince, Thomas et al. (2015) Scavenger receptor SREC-I mediated entry of TLR4 into lipid microdomains and triggered inflammatory cytokine release in RAW 264.7 cells upon LPS activation. PLoS One 10:e0122529
Murshid, Ayesha; Borges, Thiago J; Calderwood, Stuart K (2015) Emerging roles for scavenger receptor SREC-I in immunity. Cytokine 75:256-60
Eguchi, Taka; Prince, Thomas; Wegiel, Barbara et al. (2015) Role and Regulation of Myeloid Zinc Finger Protein 1 in Cancer. J Cell Biochem 116:2146-54
Chou, S-D; Murshid, A; Eguchi, T et al. (2015) HSF1 regulation of β-catenin in mammary cancer cells through control of HuR/elavL1 expression. Oncogene 34:2178-88
Murshid, Ayesha; Gong, Jianlin; Ahmad, Ridwan et al. (2015) Scavenger receptor SREC-I promotes double stranded RNA-mediated TLR3 activation in human monocytes. Immunobiology 220:823-32
Calderwood, Stuart K; Murshid, Ayesha (2015) Siglecs take a TOLL on inflammation: deciphering the Hsp70 riddle. EMBO J 34:2733-4

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