Designing novel therapeutic strategies for ovarian cancer requires understanding chemoresistance molecular mechanisms. MyD88 plays a critical role in cancer. MyD88 knockout mice (MyD88-/-) are resistant to various carcinogen-induced cancers, and MyD88 expression correlates with negative survival of ovarian cancer patients. All Toll-like receptors (TLRs), but TLR3, signal through MyD88, which triggers the production of proinflammatory cytokines. TLRs are pattern recognition receptors (PRRs) that recognize both conserved pathogen-associated molecular patterns (PAMPs) and endogenous danger signals (DAMPs). TLR ligands have been used in clinics as immunostimulatory molecules in combination with anticancer treatments, but they can evoke either beneficial or deleterious effects. Reasons explaining these contradictory results include the binding of Paclitaxel, one of the main chemotherapeutic drugs used against ovarian cancer, to TLR4, and the existence of TLR4 variants linked with cancer risk. No link has been described as yet between TLR variants and ovarian cancer. Our long term goal is to develop personalized therapeutic strategies to prevent and/or overcome cancer chemoresistance. The objective of the studies herein is to identify TLR variants expressed by tumor-infiltrating immune cells that can mediate damage chain reaction after engagement by Paclitaxel and/or tumor-released DAMPs. Our central hypothesis is that chemotherapy can re-program tumor-infiltrating immune cells through the engagement of TLR variants by PAMPS and tumor-released DAMPs, leading to tumor rejection or chronic inflammation, damage chain reaction and chemoresistance, depending on the patients'TLR variants. The rationale is that the identification of TLR variants that promote tumor rejection or chronic inflammation in reaction to chemotherapy will permit to design personalized treatments and greatly improve patient prognosis. This hypothesis will be tested by pursuing two specific aims: 1) Identification of donors prone to damage chain reaction by screening peripheral blood lymphocytes for functional polymorphism in reaction to Paclitaxel and tumor-released DAMPs. Phenotype and functional changes of immune cells from 200 healthy donors will be characterized after co-culture with chemosensitive and chemoresistant ovarian tumor cells in presence of Paclitaxel;2) [deletion of previous aim#2] Study of TLR snp association in serous ovarian cancer specimens that are linked to clinical data related to chemotherapy responses and clinical outcome. The approach is innovative because it proposes to examine ovarian cancer chemoresistance as a consequence of the specific engagement by Paclitaxel and tumor-released DAMPs to constitutive TLR variants on immune cells. This research is significant because, if successful, it will enable the design of personalized therapeutics targeted against DAMPs to block aberrant binding to TLR variants, thus chronic inflammation, therefore enabling patient responses to chemotherapeutic drugs.
The proposed research is relevant to public health because it proposes to identify constitutive molecular variants of toll-like receptors (TLR variants) that can be activated by tumor cell debris (DAMPs) generated by chemotherapeutic drugs, leading to chronic inflammation in the tumor microenvironment, tumor growth and chemoresistance. The project includes 1/ in vitro functional studies and TLR sequencing of immune cells from healthy donors to link TLR variants with DAMP-dependant functional polymorphisms, and 2/ [deletion of previous aim#2] identifications of TLR single-nucleotide polymorphisms linked to ovarian cancer chemoresistance using The Cancer Genome Atlas (NCI) bank. The proposed research is relevant to NIH's mission to developing fundamental knowledge that can translate into screening tests enabling cancer early detection and personalized anti-cancer therapy.
