Understanding T-Cell Senescence to Optimize Ovarian Cancer Immunotherapy
Abstract
Project Hypothesis and Rationale: Despite modern efforts for aggressive surgery and combination chemotherapy, high-grade serous ovarian cancer (HGSOC) remains incurable. HGSOCs are often enriched by tumor-specific infiltrating lymphocytes (TILs) and patients with cancer that contain TILs at diagnosis live longer. Immunotherapy has shown curative efficacy in melanoma and hematological malignancies and can be applied in HGSOC. However, due to their highly disseminating peritoneal nature, ovarian tumors harbor inherent intratumoral heterogeneity which combined with therapeutic pressure from chemotherapy or subsequent PARP inhibitors (PARPi), can make the evolution of TIL infiltration challenging to predict. The temporal evolution of TIL infiltration under long-term chemotherapy or PARPi has not been comprehensively documented, and the precise mechanisms of enhanced immune reactivity or immune escape at baseline or under DNA-damaging therapeutic pressure remain unclear. My hypothesis is that tumor progression combined with systemic platinum chemotherapy or PARPi induces T cell senescence due to accumulated genotoxic stress. Being able to understand the impact and potentially deleterious effects of chemotherapy and PARPi in T cell-senescence can guide the rational design of immunotherapy-based approaches with the overarching goal to improve survivorship of ovarian cancer patients. This is of particular importance for the application of immunotherapy such as immune checkpoint blockade (ICB) which aim to (re)activate T cell immunity. Career Goals in Ovarian Cancer Research: My career goal is to develop an independent, internationally recognized, externally funded and competitive research program in ovarian cancer immunobiology. Specifically, I aspire to (1) elucidate the evolution of T cell immunity under the effect or PARP inhibitors (PARPi) and chemotherapy with the overarching goal to improve ovarian cancer immunotherapy; (2) translate biological lessons stemming from my mechanistic work into therapeutic interventions to improve patients’ survival; and (3) develop leadership and grantsmanship skills as well as a competitive, well-funded, stimulating research environment that facilitates scientists to pursue their scientific passion in ovarian cancer research. My research proposal supported by my career development and sustainment plan in concordance with a strong mentorship and guidance are all aligned to make this application successful and achieve my career goals. The award of this OCA award will be indispensable for its realization and for my development as an independent ovarian cancer researcher. Commitment to the OCA and OCRP Mission: The above, together with the possible award of this proposal, will provide me with resources to continue my research in the forefront of ovarian cancer as well as to expand my networking and collaborative opportunities that will sustain a long, successful and independent career. The mission of my research proposal and career plan is well aligned with that of Ovarian Cancer Research Program to support the investigation of patient-centered questions in order to improve treatments and ultimately cure ovarian cancer. My participation in the Ovarian Cancer Academy will enrich the community via potential collaboration with unique reagents and material and via knowledge dissemination in presentations of OCA meetings as well as scientific publications. Applicability of Research Proposal: My research proposal is highly relevant to the American and international public, including patients but also their families, and is expected to (1) advance our knowledge of the evolution of ovarian cancer T cell immunity, (2) advance ovarian cancer research, and ultimately, (3) improve the health of patients with chemotherapy-sensitive and chemotherapy-resistant ovarian cancer. Its implementation, within the duration of this award, will potentially explain why only few ovarian cancer patients
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210703
Entities
People
- Denarda Dangaj Laniti
Organizations
- Lausanne University Hospital
- United States Army