| Summary: | T-cell immunology has become a central focus for research in the fight
against cancer. To mount an effective antitumor activity, T-cells migrate to and
infiltrate into the tumor, proliferate, secrete cytokines and differentiate into
specialized T-helper (Th) subsets. However, the tumor microenvironment (TME)
presents a major challenge to tumor-infiltrating T-cells. Dying necrotic cancer
cells release potassium (K+), the main intracellular cation, leading to a 10-fold
increase in the extracellular K+ concentration ([K+]e) within the local
microenvironment. This results in an accumulation of intracellular K+ ions ([K+]i)
in T-cells, causing them to be immunosuppressed. The implications of exposure
to a K+-rich microenvironment on T-cell effector function remain poorly
understood. The goal of this interdisciplinary thesis was to investigate functional
impact of high-[K+]e on T-cells and develop a strategy that could rescue T-cells
from high-[K+]e-mediated immunosuppression. In aim 1, we characterized the
effect of high-[K+]e on T-cell motility. Findings revealed that exposure to high-
[K+]e inhibited T-cell motility and chemotaxis by impairing the LFA-1-mediated
signal transduction pathway, interfering with cytoskeletal regulators and
downregulating the chemokine receptor, CXCR4. In aim 2, we investigated
whether and how high-[K+]e affects T-cell effector function. Findings showed that
exposure to high-[K+]e perturbed T-cell proliferation and cytokine production by
dysregulating T-cell receptor/co-receptor signaling pathways and metabolism
that ultimately skewed T-cell differentiation towards Th2 and regulatory T-cell
(Treg) subsets that favor tumor growth while restricting antitumor Th1 and Th17
subsets. Biopsies from patient-derived HCC/CRC tumors showed similar
phenotypes. In aim 3, we designed, synthesized and biologically evaluated a
panel of novel thiazoloquinolin-2-amine derivatives as KCa3.1 channel activators.
We identified SKA-346 as a KCa3.1-selective activator with an in vitro EC50 of
1.9 μM and an in vivo circulating half-life (t1/2) of 2.8 h. Overall, the current thesis
significantly broadens the understanding of the immunosuppressive TME.
Results presented here have implications for future therapeutic advancements and
underscore the potential of SKA-346 in augmenting the antitumor immune
response.
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