Browsing by Subject "Immune Checkpoint Blockade"

The adaptive immune system plays a crucial role in combating tumors through immunosurveillance and responding to immunotherapies. However, many studies investigating the anti-tumor immune response focus primarily on tumor-infiltrating lymphocytes (TILs), which often lack specificity for the antigenic epitopes presented on tumor cells, making them less relevant for effective anti-tumor immunity. To gain insights into novel immunotherapeutic targets and biomarkers of response, it is essential to characterize the phenotypic features and dysfunctional mechanisms of tumor-specific T cell populations. This requires the use of tumor models that express known neoantigens in order to study tumor-specific T cell responses in vivo. While transplant models with known neoantigen expression are widely used, there is a limitation in the availability of autochthonous tumor models where the tumor coevolves with the immune system. In this dissertation, various approaches to studying the tumor-specific immune response in the autochthonous setting are presented and discussed. One such approach that has been developed involves combining CRISPR/Cas9 and sleeping beauty transposase technology to create an autochthonous orthotopic murine sarcoma model. This model incorporates key genetic elements such as oncogenic KrasG12D, functionally impaired p53, and the expression of known MHCI and MHCII sarcoma neoantigens. By utilizing MHC tetramer flow cytometry, a tumor-specific immune response in the peripheral blood was identified as early as 10 days after tumor induction, leading to effective tumor clearance. Interestingly, when CD8 and CD4 T cells were co-depleted, tumors developed at a high penetrance. However, depleting either CD8 or CD4 T cells alone was insufficient to permit tumor growth. These findings indicate that both CD8 and CD4 T cells can independently contribute to immunosurveillance and participate in the clearance of sarcomas expressing MHCI and MHCII neoantigens. Understanding the tumor-specific immune response in autochthonous models is crucial for uncovering new targets for immunotherapy and identifying biomarkers of response. The development of the autochthonous orthotopic murine sarcoma model described in this dissertation provides a valuable tool for investigating the mechanisms and characteristics of tumor-specific T cell responses in an in vivo setting.

Glioblastoma (GBM) is the most common primary malignant brain tumor. Despite standard of care treatment GBM remains universally lethal, demonstrating a significant need for newer treatment strategies such as immunotherapy. Immune checkpoint blockade is a type of immunotherapy which seeks to perpetuate T cell activity by blocking inhibitory immune checkpoints. This strategy has gained FDA approval in several solid tumors, yet has failed in GBM. Severe T cell dysfunction such as T cell exhaustion is a known contributor to failures of immune checkpoint blockade, yet has not been thoroughly described in GBM. In this dissertation, we explore T cell exhaustion as a contributor to immune checkpoint blockade failure in GBM. Chapters 1-3 provide a comprehensive review of several distinct modes of T cell dysfunction in GBM including the importance of T cell exhaustion. In Chapter 4 we demonstrate severe bona fide T cell exhaustion in patients with GBM. In Chapter 5 we explore 4-1BB agonism as a means to prevent T cell exhaustion and thus sensitize GBM to immunotherapeutic strategies. In Chapter 6 we describe the mechanism driving T cell exhaustion and reveal a novel mechanism by which T cell based immunotherapies may recognize and kill tumor cells. In summary, this original work provides several encouraging insights for the development and evaluation of immunotherapeutic strategies, particularly immune checkpoint blockade, in GBM.