Problem/Issue Addressed: The intricacies of CD8+ T cell behavior within the liver, especially at the single-cell level, remain largely unexplored. These cells are vital in neutralizing intracellular pathogens and tumors in the liver. Their efficacy is hinged on their capacity to traffic within the liver, recognize antigens, activate, and manifest their effector functions.
Importance for Society: Comprehending the dynamics of intrahepatic CD8+ T cells is crucial as it offers avenues for the development of enhanced vaccination and innovative immunotherapeutic strategies, addressing infectious diseases and cancer.
Overall Objectives:
1. Understand how factors in hepatocellular carcinomas influence CD8+ T cell behavior and function.
2. Examine intrahepatic T cell priming events resulting in functionally compromised T cell responses.
Conclusions of the Action:
Aim 1: Our innovative mouse model, replicating the salient features of human hepatocellular carcinoma, revealed pivotal insights into CD8+ T cell behavior within tumors. Specifically, we discovered that the antitumor potential of these effector CD8+ T cells diminishes notably when tumor lesions grow beyond a size of 100 mm3. Our research pinpointed the causal factors: larger lesions ("non-responder lesions") presented obstacles to effective antigen recognition and subsequent T cell activation, in contrast to smaller lesions ("responder lesions"), which retained a more receptive environment. A crucial breakthrough was understanding the endothelial transformation in primary liver cancers, characterized by the shift from fenestrated liver sinusoidal endothelial cells (LSECs) to capillarized ones, fundamentally altering the immunosurveillance capabilities of CD8+ T cells. This alteration proposes the potential of reprogramming endothelial cells to improve immune responses within larger tumors, paving the way for enhanced efficacy of treatments like CAR T cells. Our research on this front is in its final stages and we're preparing to present our findings to a prestigious journal.
Aim 2: As detailed in Benechet et al., Nature 2019, and De Simone et al., Immunity 2021, we found that hepatocyte-primed T cells demonstrated unique dysfunctional attributes. This dysfunctional state, while resistant to conventional treatments like anti-PD-L1, responded to IL-2, presenting an avenue for therapeutic intervention. Collaborative efforts led to the development of a targeted IL-2 based therapeutic, uniquely activating the IL-2 pathway in CD8+ T cells, without the pleiotropic effects seen in other immune cells. The effectiveness of this approach in treating chronic HBV was underscored by its ability to significantly bolster the HBV-reactive CD8+ T cells, enhancing their antiviral activity, as evidenced in our mouse models and cynomolgus monkey studies. This therapeutic trajectory provides hope for innovative treatments targeting chronic HBV and potentially other conditions.
In conclusion, the grant facilitated pivotal advancements in our understanding of intrahepatic CD8+ T cell dynamics. Through rigorous research, we not only unveiled key behavioral patterns but also paved the way for novel therapeutic strategies. Each facet of our proposed objectives has been addressed in depth, pushing the boundaries of current scientific knowledge and setting the stage for future breakthroughs.
