Targeting Stemlike CD8 T Cells in Immunotherapy Against Kidney Cancer
Abstract
Hypothesis, Evidence, and Rationale: CD8 T cells are essential for controlling tumor growth. However, in Renal Cell Carcinoma (RCC) and most other cancers, antitumor CD8 T cells become exhausted. Exhausted CD8 T cells are impaired in their function, proliferation and persistence due in part to upregulation of inhibitory receptors (i.e., immune checkpoints) including PD1. Immunotherapies with immune checkpoint inhibitors (ICI) aim at reinvigorating exhausted T cells. Yet, less than 30% of RCC patients responded to ICI treatment, only a minority of whom experienced complete responses. The molecular program of T cell exhaustion is largely unaffected by ICIs and contribute to the lack of durable control of RCC in ICI-treated patients. CD8 T cells with stem cell characteristics were recently found in tumors including RCC. Unlike terminally exhausted CD8 T cells, stem-like CD8 T cells resist exhaustion and respond potently to ICIs. In addition, the abundance of stem-like T cells predicted favorable clinical outcomes in ICI therapy for melanoma patients. Thus, enhancing the immune response by stem-like CD8 T cells may improve the efficacy of ICIs in RCC patients. My recent studies revealed the transcriptional and epigenetic mechanisms underlying T cell stemness and T cell exhaustion. However, how the antitumor response of stem-like CD8 T cells is regulated in RCC and strategies to improve the efficacy of ICCs in RCC via targeting stem-like CD8 T cells remain elusive. In addition, the prognostic value of stem-like CD8 T cells in RCC patients treated with ICIs is unclear. In this study, I will test the hypothesis that the therapeutic efficacy of ICIs against RCC is determined by the quantity, metabolic fitness and tumor microenvironment (TME) of stem-like CD8 T cells. I will conduct this study under the supervision of Drs. Simon and Brugarolas and leverage the rich resources in patient samples and mouse RCC models in University of Texas Southwestern Medical Center at Dallas Kidney Cancer Program (KCP) and expertise of my mentors/collaborators in single-cell multi-omics, machine learning of pMHC-TCR interaction, metabolism, TME, and image mass cytometry. In Aim 1, I will determine the antigen specificity and differentiation status of antitumor CD8 T cells in human RCC and evaluate whether the abundance and transcriptome of antitumor stem-like CD8 T cells predict clinical outcomes of PD1 blockade in RCC patients. I will also evaluate strategies to potentiate the therapeutic efficacy of ICI against RCC using a therapeutic vaccine that induces robust expansion of stem-like CD8 T cells. In Aim 2, I will investigate the mechanism underlying the synergistic effect between tyrosine Kinase Inhibitor (TKI) and ICI. I will leverage single-cell metabolism assay to determine how TKI modulates the metabolism of antitumor stem-like CD8 T cells and whether TKI promotes formation of immunostimulatory intra-tumoral niche for stem-like CD8 T cells in mouse and human RCC. Career Goals in Kidney Cancer Research: My overarching career goal is to establish a sustainable and robust research program focusing on the molecular and cellular mechanisms governing the immune response of T cell against RCC and apply the knowledge gained from basic research to developing novel immunotherapies for RCC patients. I plan to discover pathways involved in T cell exhaustion and pathways that endow stem-like T cells the ability to resist exhaustion in RCC. In collaboration with Dr. Brugarolas, I hope to develop animal models that better recapitulate human RCC and use these models to evaluate combination therapies that target pathways governing T cell stemness and/or exhaustion to enhance control of RCC. In addition, I will leverage the immense resources including clinical and omics data and samples from RCC patients treated in KCP and develop decision-guiding biomarkers, especially immune biomarkers. The Academy of Kidney Cancer Investigators (A
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310801
Entities
People
- Chen Yao
Organizations
- United States Army
- University of Texas Southwestern Medical Center