Valencia Watson

BioE Ph.D. Proposal Presentation

1:00 PM, Friday, April 19, 2024

Location: Molecular Sciences and Engineering; Room G021

Teams Meeting Link: https://teams.microsoft.com/l/meetup-join/19%3ameeting_NDJhYWQ2MzAtNDJjZS00YzFlLTlkZmEtZWM4ODU1Y2VhYjcy%40thread.v2/0?context=%7b%22Tid%22%3a%22482198bb-ae7b-4b25-8b7a-6d7f32faa083%22%2c%22Oid%22%3a%2274e7bdf0-8445-4095-940b-c7a500a408bb%22%7d

Advisors:

Dr. Cheng Zhu, Ph.D. (BME, Georgia Institute of Technology & Emory)

Committee:

Dr. Edward Botchwey, Ph.D. (BME, Georgia Institute of Technology & Emory)

Dr. Nicole Schmitt, M.D. (Department of Otolaryngology, Emory University)

Dr. Karmella Haynes, Ph.D. (BME, Georgia Institute of Technology & Emory)

Dr. John Blazeck, PhD. (Chemical & Biomolecular Engineering, Georgia Institute of Technology)

Mechanisms of impaired T cell antigen sensing in TP53 mutation expressing cancers, and the co-agonist effect of Wild Type (WT) p53 self-antigen

Immunotherapy is becoming increasingly more popular as a treatment option for cancer, especially in patients with chemotherapy resistant tumors. Although immunotherapy has been highly bought into as a treatment option for cancer patients, product efficacy is low. Taking interest in the rising occurrence of head and neck squamous cell carcinoma (HNSCC), consider anti-PD-1 (α-PD1), for example. α-PD1 is an FDA approved ICB treatment for metastatic HNSCC, but a marginal percentage of patients respond to treatment. Immunotherapies such as α-PD1, provide a future in cancer therapy that aims to reduce the toxic side effects of chemotherapy, however, further insight into TME immunosuppression is required to improve the efficacy of these treatment methods.

To advance the knowledge of TME immunosuppression, this study will focus on cytotoxic T cells, as they are integral in tumor clearance. CD8+ T cells are presented antigens in a histocompatibility complex (MHC) manner. The T cell receptor (TCR) forms a bond with the epitope presented in the binding groove of the major histocompatibility complex (pMHC). T cells exert endogenous forces on TCR–pMHC bonds to amplify antigen sensing. To bind pMHC, TCR experiences a conformational change. In the inactive TCR conformation, cholesterol binds the TCRβ subunit to allosterically regulate its function. Manipulation of cholesterol may enhance the anti-tumor immune response of cytotoxic T cells by unknown mechanisms. Recently, our lab demonstrated melanoma TME induces impaired T cell antigen response. We aim to expand these findings to determine if impaired TCR antigen recognition is conserved in other cancer types, test whether targeting cholesterol can restore TCR antigen recognition, and to identify TME immunosuppressive factors that may be contributing to this apparent loss in function. It is hypothesized that reduced TCR antigen response will be seen in other cancer types and can be recovered through cholesterol inhibition.

TCR based precision adoptive cell therapy has also demonstrated potential as a treatment option for cancer patients with tumors expressing tumor suppressor protein TP53 gene mutations. Still, extensively more work needs to be done to better characterize the TCR tumor antigen (neoantigen) response and improve clinical outcomes. We aim to advance the understanding of p53 mutant reactive TCRs and make contributions towards the development of parameters needed to determine their efficacy in ACT. Studies on ACT and other forms of immunotherapy suggest that TCR affinity, force, and downstream signaling are critical for optimal T-cell function and anti-tumor immune responses30.  We aim to explore differences in the affinity, signaling and mechanosensing of 5 patient-derived, R175H hot spot mutant reactive, TCRs to self vs. mutated ligand. We hypothesize that non-stimulatory wild-type (WT) p53 peptide will enhance binding of TCR to antigen via CD8.