Project Summary/Abstract
Immune checkpoint inhibitors (ICI’s) represent a paradigm shift in cancer care, leveraging the immune system
to target cancer cells. In animal and basic studies, these pathways (PD-1, PD-L1 and CTLA-4) are also critical
negative regulators of atherosclerosis and blockade of PD-1, PD-L1 and CTLA-4 in animal studies activates T
cells leading to T cell infiltration and increased atherosclerosis. We provide retrospective clinical and imaging
data to support our hypothesis that ICI’s will increase coronary atherosclerosis in a prospective study. We will
test this hypothesis by performing a prospective observational coronary CTA study, where 135 patients (initially
enrolling 300) with melanoma, with and without the BRAF mutation (2:1 ratio, ICI/BRAF), will undergo serial
coronary CTA at baseline, 12 months (sub-group) and 2 years. Patients with melanoma with a BRAF mutation
receive BRAF inhibitors and will act as the control group, while BRAF negative patients are treated with an ICI.
In Aim 2, based on prior work, we will test whether pre-specified plausible biological factors with established
associations with plaque progression (e.g. PD-1, PD-L1, sCD163, sCD14, MCP-1, IL-6, IL-1b) mediate the
accelerated atherosclerosis with ICI’s. For example, lower PD-1 and PD-L1 levels associate with higher
coronary atherosclerotic plaque where both PD-1 and PD-L1 suppress T cell–driven inflammation in plaques
and plaque progression. In Aim 3, we will perform unbiased exploratory analyses applying single-cell RNA
technologies to systematically decipher the immune cells that contribute. In patients, not on an ICI, specific T
cell subsets have been linked to atherosclerosis and, in preliminary data, we show activation of specific T cells
(CD8+) with other ICI toxicities. The use of ICI’s has increased and continues to rapidly expand. It is estimated
that 36% of cancer patients are currently eligible for an ICI and the number of active clinical trials leveraging
ICIs is extraordinary. Therefore, there is an urgent need to test in a clinical study whether ICI’s lead to
accelerated coronary atherosclerosis and to provide insight into the mechanisms involved.