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American Heart Association

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Final ID: Or120

CD40 is an immune checkpoint regulator that potentiates myocardial inflammation through activation and expansion of CCR2+ macrophages and CD8 T-cells

Abstract Body: Novel immune checkpoint therapeutics including CD40 agonists have tremendous promise to elicit antitumor responses in patients resistant to current therapies. Conventional immune checkpoint inhibitors (PD-1/PD-L1, CTLA-4 antagonists) are associated with serious adverse cardiac events including life-threatening myocarditis. However, little is known regarding the potential for CD40 agonists to trigger myocardial inflammation or myocarditis. Here, we leveraged genetic mouse models, single cell sequencing, and cell depletion studies to demonstrate that an anti-CD40 agonist antibody reshapes the cardiac immune landscape through activation of CCR2+ macrophages and subsequent recruitment of effector memory CD8 T-cells. We identify a positive feedback loop between CCR2+ macrophages and CD8 T-cells driven by IL12b, TNF, and IFN-γ signaling that promotes myocardial inflammation and show that prior exposure to CD40 agonists sensitizes the heart to secondary insults and accelerates LV remodeling. Collectively, these findings highlight the potential for CD40 agonists to promote myocardial inflammation and potentiate heart failure pathogenesis.
  • Jimenez, Jesus  ( Washington University School of Medicine in St. Louis , Saint Louis , Missouri , United States )
  • Amrute, Junedh  ( Washington University School of Medicine in St. Louis , Saint Louis , Missouri , United States )
  • Ma, Pan  ( Washington University in St. Louis , Saint Louis , Missouri , United States )
  • Wang, Xiaoran  ( Washington University School of Medicine in St. Louis , Saint Louis , Missouri , United States )
  • Dai, Raymond  ( Washington University in St. Louis , Saint Louis , Missouri , United States )
  • Lavine, Kory  ( Washington University School of Medicine in St. Louis , Saint Louis , Missouri , United States )
  • Author Disclosures:
    Jesus Jimenez: No Answer | Junedh Amrute: DO NOT have relevant financial relationships | Pan Ma: DO NOT have relevant financial relationships | Xiaoran Wang: No Answer | Raymond Dai: No Answer | Kory Lavine: DO have relevant financial relationships ; Advisor:Implicit biosciences:Active (exists now) ; Research Funding (PI or named investigator):Implicit Biosciences:Active (exists now) ; Research Funding (PI or named investigator):Bitterroot:Active (exists now) ; Research Funding (PI or named investigator):Novartis:Active (exists now) ; Research Funding (PI or named investigator):Amgen:Active (exists now)
Meeting Info:

Basic Cardiovascular Sciences

2024

Chicago, Illinois

Session Info:

GS10. Outstanding Early Career Investigator Award

Wednesday, 07/24/2024 , 11:00AM - 12:00PM

General Session

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CD40 is an immune checkpoint regulator that potentiates myocardial inflammation through activation and expansion of CCR2 macrophages and CD8 T-cells

Jimenez Jesus, Amrute Junedh, Ma Pan, Wang Xiaoran, Dai Raymond, Lavine Kory

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