Aim: Immune checkpoint inhibitors (ICI) are antibodies against co-inhibitory molecules CTLA-4, PD-1 and PD-L1 that have revolutionized cancer treatment. ICI release the natural brake on T cell activation, thereby enhancing anti-tumor T cell responses, but also trigger immune related adverse events, such as cardiotoxicity. As more patients are now receiving long-term ICI treatment, side effects that resemble chronic inflammatory diseases, such as atherosclerosis, could be associated with long-term ICI treatment. Therefore we studied the effect of combined αCTLA-4 and αPD1 antibodies on experimental atherosclerosis.

Methods: 12 weeks-old male Ldlr-/- mice on a 0.15% cholesterol diet were treated biweekly with αCTLA-4 and αPD1 antibodies or isotype control antibodies for 5 weeks. 

Results: Flow cytometry demonstrated a relative increase in splenic CD3+, CD3+CD4+ and CD3+CD8+ cells. CD62L-CD44+ CD4+ and CD8+ effector cells were increased, whereas CD62+CD44-  naïve T cells were decreased in ICI mice, reflecting a more activated T cell phenotype in ICI treated mice. Histology of the lung, heart and colon showed increased numbers of T cell infiltration in ICI mice. Systemic inflammation by ICI treatment was confirmed by significant increases of the pro-inflammatory markers IL-6 and IL-18 in serum.

Atherosclerotic plaque area in the aortic arch was not affected, however ICI treatment accelerated plaque progression, as indicated by Virmani classification and a significant increase in necrotic core formation. Immunohistochemistry revealed a 200% increase of the fraction of CD8+CD3+ T cells after treatment, whereas the amount of CD4+CD3+ T cells was not altered. MAC3+ plaque area was decreased after ICI treatment. 

ICI treated mice showed increased levels of the endothelium activation markers ICAM and VCAM in the abdominal aorta wall, indicating a potentially higher trans epithelial migration rate which could explain the high levels of T cell infiltration.

Conclusion: Short-term ICI treatment aggravates atherosclerotic plaque progression and inflammation, and may thereby trigger cardiovascular diseases in cancer patients.

01 - CARDIOVASCULAR ONCOLOGY: EXPLORING THE EFFECTS OF IMMUNE CHECKPOINT INHIBITORS ON EXPERIMENTAL ATHEROSCLEROSIS