The Role of TCR Engagement Strength in Antitumor CD8 T Cell Exhaustion

<p>Durability of an antitumor immune response is mediated in part by the persistence of progenitor exhausted CD8 T cells (Tpex). Tpex serve as a source for the pool of effector T cells that tend to have a short lifespan or eventually become dysfunctional in uncleared tumors. In contrast to the short-lived feature of their daughter cells, Tpex are able to preserve their quantity and developmental potential through a process of self-renewal. Previous research has demonstrated that Tpex can even self-renew in the absence of their cognate antigen. However, it remains unknown how T cell receptor (TCR) engagement impacts the self-renewal capacity of Tpex in settings of continued antigen exposure. Given that many cancer cells lack antigens capable of effectively engaging with TCRs, it is important to understand whether and how TCR engagement strength regulates the preservation of Tpex and their terminal differentiation during tumor progression. To investigate this, I established multiple murine tumor models, including Lewis lung carcinoma, which elicit an optimal or attenuated TCR signal in CD8 T cells. Longitu- dinal phenotyping and single-cell transcriptomics of tumor-specific T cells revealed that formation and maintenance of the Tpex reservoir in tumor-draining lymph nodes (tdLN) is dependent on optimal TCR engagement. Despite the generation of central memory-like T cells in tdLN under suboptimal priming, replenishment of tumor-infiltrating Tpex is abrogated. Moreover, adoptive transfer of optimally primed Tpex into a tumor setting with attenuated TCR stimulation significantly accelerates their terminal differentiation. This TCR-reinforced Tpex development and self-renewal is coupled to proximal position- ing to dendritic cell niches and epigenetic imprinting that involves increased chromatin accessibility at Egr2 and Tcf1 target loci. Collectively, my dissertation work reveals a previously unappreciated and coun- terintuitive role of TCR stimulation in preserving Tpex and highlights TCR-dependent self-renewal of Tpex during tumor progression. These results provide fundamental insight into T cell exhaustion and have important implications for the development of cancer vaccines that target tumor-epitopes with varying TCR binding avidities.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomedical Sciences

Year dc:date.available

2023

Author dc:creator

• Lan, Xin

Contributors dc:contributor

• Benjamin Youngblood, PhD

• antitumor CD8 T cells;epigenetic regulation;T cell exhaustion;TCR signal strength;Tpex self-renewal
• Medicine and Health Sciences

Repository record dc:identifier

https://dc.uthsc.edu/dissertations/665

OAI identifier oai:identifier

oai:dc.uthsc.edu:dissertations-1665