Date of Award

5-12-2024

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Exercise Science

Advisor(s)

Joon Young Kim

Keywords

atherosclerosis;immune checkpoint inhibitors;immunotherapy;lipid lowering

Abstract

Immune checkpoint inhibitors (ICIs) confer potent antitumor benefits, thereby improving the prognosis of many patients with cancer. PD-1 and CTLA-4 inhibitors are the most commonly used ICIs in a clinical setting. Treatment with PD-1 and CTLA-4 inhibitors may exacerbate atherosclerosis, a chronic inflammatory disease of the large arteries characterized by lipid accumulation. Most cancer patients, particularly those with lung cancer, present with subclinical/preexisting atherosclerosis, which is typically treated with lipid lowering strategies (e.g., low cholesterol diet) concurrently with their cancer treatment, such as ICIs. However, the concomitant use of lipid lowering and ICIs in clinical practice has not yet been reflected in the current pre-clinical literature.Therefore, we sought to investigate the effects of PD-1 and CTLA-4 and their combinations on atherosclerosis in Ldlr-/- mice within an experimental model of Halted Progression where progression is halted through lipid lowering via a standard chow diet. Mice were intraperitoneally injected with ICIs and their respective isotypes bi-weekly for four weeks, following 17 weeks on a high-cholesterol Western diet (WD), while maintained on a chow diet. We analyzed atherosclerotic plaque characteristics, comprising lipid accumulation, plaque area and morphology, and macrophage and T cells using staining techniques. PD-1 inhibition increased T cell mediated atherosclerotic plaque progression towards a phenotype resembling unstable, clinically unfavorable plaques in humans, irrespective of lipid lowering. CTLA-4 inhibition increased plaque progression towards characteristics associated with stability and clinical favorability in humans, such as increased collagen content and calcification. The combined inhibition of PD-1 and CTLA-4 did not generate proatherogenic effects, yet promoted a phenotype indicative of stability in humans, characterized by increased cap thickness, reduced lipid accumulation, and a decrease in immune cell presence within the intima. While direct extrapolation to clinical settings remains challenging, the insights gained from our experimental atherosclerosis model elucidate the intricate effects of ICIs on atherosclerotic processes. This underscores the need to explore the synergistic potential of combining immunotherapies with lipid lowering strategies, aiming for improved CV outcomes in cancer patients.

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Open Access

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