Mechanisms of T Cell Dysfunction in Chronic Lymphocytic Leukemia and Viral Associated Carcinoma
Creators: Bozorgmehr, Najmeh
Publisher: name: University of Alberta Library
Year: 2023

<p>T cell exhaustion compromises anti-tumor immunity, and a sustained elevation of coinhibitory<br>
receptors is a hallmark of T cell exhaustion in solid tumors. Similarly,<br>
upregulation of co-inhibitory receptors has been reported in T cells in hematological<br>
cancers such as chronic lymphocytic leukemia (CLL). CD8+ T cells play an essential<br>
role against tumors, but mechanisms associated with their exhaustion in various<br>
cancers are diverse and yet to be elucidated. This research study evaluates the<br>
mechanism(s) associated with CD8+ T cell phenotype and function in CLL and<br>
immunotherapy-related immune signatures in HPV-associated (Human Papilloma<br>
Virus) carcinoma.<br>
First, I examined the expression of different co-inhibitory receptors in CD8+ T cells<br>
obtained from peripheral blood/bone marrow of CLL patients by flow cytometry. I<br>
found CD160 as the most dominant co-inhibitory receptor in these patients. Its<br>
expression was associated with an exhausted T cell phenotype, and CD160+CD8+ T<br>
cells were highly antigen-experienced T cells. Furthermore, we proposed chronic<br>
stimulation, CD160-containing EVs, and elevated IL-16 levels as mechanisms linked<br>
to the expansion of CD160-expressing CD8+T cells in CLL.<br>
Moreover, I found a significant decline in CD26 expressing CD8+ T cells in CLL<br>
compared to healthy subjects. My findings demonstrated that CD26high cells were<br>
enriched with Mucosal Associated Invariant T (MAIT) cells co-expressing CD161,<br>
TV7.2, and IL-18R. Also, I observed that CD26high cells have a rich chemokine<br>
receptor profile (e.g., CCR5 and CCR6), profound cytokine (TNF-, IFN-, and IL-2),<br>
and cytolytic molecules (Granzyme B, K, and perforin) expression upon stimulation.<br>
Overall, my results demonstrate that CD26+ T cells possess a natural<br>
polyfunctionality to traffic, exhibit effector functions, and resist exhaustion. In turn,<br>
Galectin-9 (Gal-9) and the inflammatory milieu (IL-18, IL-12, and IL-15) in CLL<br>
patients contribute to the depletion of CD26high T cells. Hence, depletion of MAIT cells<br>
may predispose CLL patients to immune dysfunction and susceptibility to infections.<br>
Furthermore, I conducted bulk RNA sequencing analysis of peripheral immune cells<br>
to gain insight into immune checkpoint blockade therapy in advanced HPV-associated<br>
carcinoma patients. I discovered that the immune cell signature in responders to<br>
immunotherapy is entirely different from non-responders at the baseline and<br>
following treatment. The genes and pathways related to myeloid immune responses<br>
were more prominent in the non-responding group, which supports their suppressive<br>
role in this group. In agreement, non-responders had higher levels of IL-8 and IL-18<br>
at the baseline than responders. In contrast, responders had higher CD8+ T cells at<br>
the endpoint.<br>
These observations highlight potential mechanisms of T cell exhaustion in<br>
hematologic malignancies such as CLL versus solid tumors. My studies have provided<br>
a novel insight into the underlying mechanism(s) of immune dysfunction with<br>
potential clinical implications for precision medicine.</p>