The most frequent loss-of-function for any TLR is the R392X variant of TLR5, which has a dominant-negative effect, affects ~7-10% of the general population, and is relevant for the function of the immune system. Here, we will elucidate for the first time how mechanisms of tumor immunosurveillance are differentially modulated in the absence of TLR5 signaling. Key experimental findings supporting this proposal have been: 1) The recognition that TLR5-deficiency confers superior immune protection against malignant progression in mice, both in terms of quality and magnitude;2) analysis of emerging data from TCGA project indicating that TLR5- deficient patients survive in higher proportions after two years of an ovarian cancer diagnosis, compared to wild-type individuals;3) the identification of a dissimilar population of ?? T cells that accelerates malignant progression in TLR5+ hosts, but exerts protective activity in TLR5-deficient individuals. Based on these and other of our findings, our central hypothesis is that TLR5-deficiency, through dissimilar interactions with commensal microorganisms (the only endogenous source of flagellin), results in significant functional differences in ?? T cells, which modulate systemic mechanisms of immune surveillance, leading to different immune protection against malignant progression.
In Aim 1, we will determine how ?? T cells influence tumor progression in wild-type vs. TLR5-deficient individuals. These results will dissect the suppressive mechanisms whereby ?? T cells generated in the presence of TLR5 signaling promote tumor growth, while their counterpart in TLR5-deficient hosts delay malignant development.
In Aim 2, we will elucidate why ?? T cells acquire a different phenotype in TLR5-deficient tumor-bearing hosts. Because the ligand of TLR5 is a bacterial product, these results will elucidate how microbiota (carriers of the only endogenous ligand) drives the differentiation of ?? T cells that determine immunosurveillance responses.
In Aim 3, we will define differences in anti-tumor immunity between human TLR5-deficient and wild-type cancer patients, using our bank of viable ovarian and breast cancer dissociated specimens. Our work will exert a profound effect in the field by elucidating how a significant segment of the general population may orchestrate different anti-tumor immune microenvironments that could make them more responsive to specific immunotherapeutic interventions. Furthermore, this research could pave the way for understanding how millions of individuals may be more susceptible (or show enhanced protection) to develop aggressive tumors in response to mutagenic events that remain asymptomatic in other people.
At least 30% of individuals in the general population are carriers of a limited set of polymorphisms in pattern recognition receptors (PRRs) genes. Although these polymorphisms are compatible with a healthy life, they are functionally relevant because the carriers'susceptibility to develop certain infectious and/or autoimmune diseases is altered. Still, how mechanisms of tumor immunosurveillance are affected in these individuals remains completely unknown. The proposed studies will exert a profound impact in the field by elucidating how 7- 10% of individuals in the general population carrying a polymorphism that inactivates TLR5 function in a dominant negative fashion respond differently to primordial mutagenic events, orchestrate superior anti-tumor immunity and, correspondingly, exhibit better prognosis. Besides providing a mechanistic rationale to establish novel prognostic models, results derived from the proposed Aims will also contribute to understand whether these carriers may be more responsive to immunotherapeutic interventions, thus providing a significant advance towards the goal of personalized Medicine.
|Rutkowski, Melanie R; Stephen, Tom L; Svoronos, Nikolaos et al. (2015) Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 27:27-40|
|Stephen, Tom L; Rutkowski, Melanie R; Allegrezza, Michael J et al. (2014) Transforming growth factor ?-mediated suppression of antitumor T cells requires FoxP1 transcription factor expression. Immunity 41:427-39|
|Li, Yun R; Xian, Rena R; Ziober, Amy et al. (2014) Mesothelin expression is associated with poor outcomes in breast cancer. Breast Cancer Res Treat 147:675-84|