Recently, we described a sub-population of epithelial ovarian cancer (EOC) cells that express Myeloid Differentiation Protein 88 (MyD88). Further characterization, revealed additional differences at molecular level suggesting a potential classification of EOC cells into Type I and Type II EOC cells. In Type I, ligation of TLR-4, with LPS, induce significantly high levels of pro-inflammatory cytokines. Moreover, these cells are more resistant to TNF? and paclitaxel-induced apoptosis, and produce cytokines in response to this agent. Furthermore, our studies also showed that the cytokines and chemokines secreted by Type I EOC cells has great impact on monocyte function. These characteristics are not observed in Type II EOC cells. Therefore, our central hypothesis is that upon recognition of signals through TLR, Type I EOC cells can release chemokines and cytokines that would "educate" immune cells to perform tumor-supportive functions. Contrary to previous hypotheses explaining the presence of immune infiltrate in the tumor microenvironment as an anti-tumor immune response, we propose that cancer cells recognize their unique microenvironment and respond to it by recruiting and educating immune cells to produce cytokines and growth factors that will promote tumor survival. The objectives of this proposal are: 1) To understand the function of TLR/MyD88/NF?B pathway in tumor cells and its impact on immune cell regulation and function;and 2) To correlate tumor MyD88 expression and patient survival.
Our specific aims are as follows: ? Aim 1. To determine the molecular mechanisms mediating the differential responses in Type I and II EOC cells ? Aim 2. To characterize Type I EOC cell-induced immune cell differentiation. ? Aim 3. To characterize the differential regulation of immune cells in vivo by Type I and II EOC cells. ? Aim 4. To determine the correlation between tumor-MyD88 expression, cytokine profile and survival in EOC patients. The studies proposed in this application provide an alternative perspective on the interaction between cancer cells and immune cells. Our observation that the expression of TLRs, and more important the expression of MyD88 in ovarian cancer cells, mediating the production of cytokines, tumor resistance to chemotherapy and immune regulation, presents a new perspective in tumor immunology that will allow the adequate design of strategies to boost the immune system against the tumor. Project Narrative This proposal seeks to determine the impact of a functional TLR/MyD88/NF?B pathway on the capacity of tumor cells to regulate immune function and confer chemo-resistance. The characterization of the cross talk between EOC cells and immune cells, which predisposes to a pro-tumor environment, will aid in the development of new approaches to enhance tumor rejection and prevent immune-induced tumor progression. In addition, the confirmation that patients with MyD88-expressing tumors should not receive paclitaxel, because its administration can actually aid on tumor progression, will significantly change the current mode of management in patients with ovarian cancer and will aid in the development of "personalized" therapy and longer patient survival.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Howcroft, Thomas K
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Yale University
Obstetrics & Gynecology
Schools of Medicine
New Haven
United States
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