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Background: Immune checkpoint inhibitors (ICI) treat an expanding range of cancers. Consistent basic data suggest that these same checkpoints are critical negative regulators of atherosclerosis. Therefore, our objectives were to test whether ICIs were associated with accelerated atherosclerosis and a higher risk of atherosclerosis-related cardiovascular events. Methods: The study was situated in a single academic medical center. The primary analysis evaluated whether exposure to an ICI was associated with atherosclerotic cardiovascular events in 2842 patients and 2842 controls, matched by age, a history of cardiovascular events and cancer type. In a second design, a case-crossover analysis was performed with an "at-risk period" defined as the two-year period after and the "control period" as the two-year prior to treatment. The primary outcome was a composite of atherosclerotic cardiovascular events (myocardial infarction, coronary revascularization and ischemic stroke). Secondary outcomes included the individual components of the primary outcome. Additionally, in an imaging sub-study (n=40), the rate of atherosclerotic plaque progression was compared from before and after starting an ICI. All study measures and outcomes were blindly adjudicated. Results: In the matched cohort study, there was a 3-fold higher risk for cardiovascular events after starting an ICI (HR, 3.3 [95% CI, 2.0-5.5]; P <0.001). There was a similar increase in each of the individual components of the primary outcome. In the case-crossover, there was also an increase in cardiovascular events from 1.37 to 6.55 per 100 person-years at two years (adjusted HR, 4.8 [95% CI, 3.5-6.5]; P <0.001). In the imaging study, the rate of progression of total aortic plaque volume was >3-fold higher with ICIs (from 2.1%/year pre-to 6.7%/year post). This association between ICI use and increased atherosclerotic plaque progression was attenuated with concomitant use of statins or corticosteroids. Conclusions: Cardiovascular events were higher after initiation of ICIs, potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk, prior to, during and after treatment, should be considered among patients on an ICI.

T lymphopoiesis requires settling of the thymus by bone marrow-derived precursors throughout adult life. Progenitor entry into the thymus is selective, but the molecular basis of this selectivity is incompletely understood. The chemokine receptor CCR9 has been demonstrated to be important in this process. However, progenitors lacking CCR9 can still enter the thymus, suggesting a role for additional molecules. Here we report that the chemokine receptor CCR7 is also required for efficient thymic settling. CCR7 is selectively expressed on bone marrow progenitors previously shown to have the capacity to settle the thymus, and CCR7 ؊/؊ progenitors are defective in settling the thymus. We further demonstrate that CCR7 sustains thymic settling in the absence of CCR9. Mice deficient for both CCR7 and CCR9 have severe reductions in the number of early thymic progenitors, and in competitive assays CCR7 ؊/؊ CCR9 ؊/؊ double knockout progenitors are almost completely restricted from thymic settling. However, these mice possess nearnormal thymic cellularity. Compensatory expansion of intrathymic populations can account for at least a part of this recovery. IntroductionAll blood lineages are derived from hematopoietic stem cells (HSCs) in the bone marrow (BM). Unlike other blood lineages, T cells continue the majority of their development outside the BM, in the thymus. As the thymus does not contain self-renewing progenitors, it must import BM-derived precursors during adult life. [1][2][3][4][5] This process can be regarded as 3 steps: generation of T-lineage progenitors in the BM, mobilization of progenitors out of the BM into the blood, and settling of blood-borne progenitors into the thymus. Thymic settling progenitors (TSPs) have not yet been definitively identified due to their presumed rarity. [6][7][8][9] After thymic settling, TSPs generate Lineage-marker (Lin)-negative, Kit ϩ CD25 -early thymic progenitors (ETPs), which constitute the earliest defined T-cell precursor population within the thymus. 4,10 ETPs in turn undergo proliferative expansion to give rise to CD4 -CD8 -Kit ϩ CD25 ϩ double-negative 2 (DN2) and CD4 -CD8 -Kit lo CD25 ϩ DN3 cells. DN3 cells undergo additional proliferation before differentiating into CD4 ϩ CD8 ϩ double-positive (DP) cells, which constitute the majority of thymocytes. DP thymocytes subsequently undergo T-cell receptor-dependent selection to generate CD4 or CD8 single-positive (SP) cells, which emigrate from the thymus to populate the periphery. 11 The BM contains multiple progenitors with T-lineage potential that may contribute to T lymphopoiesis. [12][13][14][15] The most primitive hematopoietic progenitors in the BM have a Lin -Sca1 ϩ Kit ϩ (LSK) phenotype and can be differentiated into subsets on the basis of expression of the cytokine receptor Flt3. These subsets include multipotent and self-renewing HSCs (LSKFlt3 -), multipotent progenitors (MPPs), which do not possess self-renewal capacity (LSKFlt3 lo ), 16 and lymphoid-primed multipotent progenitors (LMPPs; LSKFlt3 hi ). 17 LM...

Aims Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented. Methods and results From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE. Conclusion These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.