Associazione Nazionale Medici Cardiologi Ospedalieri

CONGRESS ABSTRACT

CONGRESS ABSTRACT

CTLA-4 and PD-1 blocking agents affects longitudinal and radial strain in preclinical models, increases systemic CXCL12, cardiac fibronectin EDA, S-100 calgranulin, galectine-3 and NLRP-3/MyD-88/chemokine pathways

Quagliariello Vincenzo Napoli (Napoli) – Istituto Nazionale Tumori-Irccs-Fondazione G. Pascale | De Lorenzo Claudia Napoli (Napoli) – Federico II | Passariello Margherita Napoli (Naples) – Università Federico II | Di Mauro Annabella Napoli (Napoli) – Istituto Nazionale Tumori-Irccs-Fondazione G. Pascale | Cipullo Ciro Napoli (Napoli) – Istituto Nazionale Tumori-Irccs-Fondazione G. Pascale | Paccone Andrea Napoli (Napoli) – Istituto Nazionale Tumori-Irccs-Fondazione G. Pascale | Iovine Martina Napoli (Napoli) – Istituto Nazionale Tumori-Irccs-Fondazione G. Pascale | Bruzzese Francesca Napoli (Napoli) – Istituto Nazionale Tumori-Irccs-Fondazione G. Pascale | Palma Giuseppe Napoli (Napoli) – Istituto Nazionale Tumori-Irccs-Fondazione G. Pascale | Luciano Antonio Napoli (Napoli) – Istituto Nazionale Tumori-Irccs-Fondazione G. Pascale | Maurea Nicola Napoli (Napoli) – Istituto Nazionale Tumori-Irccs-Fondazione G. Pascale

Background: Immune checkpoint inhibitors (ICIs) have significantly changed the oncology clinic in recent years, improving survival expectations in cancer patients. ICI therapy have a broad spectrum of side effects from endocrinopathies to cardiovascular diseases. In this study, pro-inflammatory and pro-fibrotic effects of short-term ICIs therapy in preclinical models were analyzed.

Methods: Firstly, in a human in vitro model, human cardiomyocytes co-cultured with hPBMC were exposed to ICIs (with CTLA-4 or PD-1 blocking agents, at 200 nM) for 72h. After treatment, production of DAMPs and 12 cytokines were analyzed in the supernatant through colorimetric and enzymatic assays. C57/Bl6 mice were treated with CTLA-4 or PD-1 blocking agents (15 mg/kg) for 10 days. Before (T0), after three days (T3) and after treatments (T10), ejection fraction, fractional shortening, radial and longitudinal strain were calculated by using bidimensional echocardiography (Vevo 2100,Fujfilm). Fibrosis, necrosis, hypertrophy and vascular NF-kB expression were analyzed through Immunohistochemistry. Myocardial expression of DAMPs (S100- Calgranulin, Fibronectin and Galectine-3), MyD88, NLRP3 and twelve cytokines have been analyzed. Systemic levels of SDF-1, IL-1β and IL-6 were analyzed before, during and after ICIs therapy.

Results: Radial and longitudinal strain were decreased after 10 days of ICIs therapy. Histological analysis of NF-kB expression shows that short-term anti-CTLA-4 or anti-PD-1 treatment increased vascular and myocardial inflammation. No myocardial hypertrophy was seen with the exception of the pembrolizumab group. Myocardial fibrosis and expression of galectin-3, pro-collagen 1-α and MMP-9 were increased after treatment with all ICIs. Both anti-CTLA-4 or anti-PD-1 treatments increased the expression of DAMPs, NLRP3 inflammasome and MyD88 and induced both in vitro and in vivo the  secretion of IL-1β, TNF-α and IL-6. Systemic levels of SDF-1, IL-1β and IL-6 were increased during and after treatment with ICIs.              

Conclusions: Short therapy with PD-1 and CTLA-4 blocking agents increases vascular expression of NF-kB,  systemic SDF-1, IL-1β, IL-6 levels and myocardial NLRP3, MyD88 and DAMPs expression in preclinical models. A pro-inflammatory cytokine storm was induced in myocardial tissues and in cultured cardiac cells after ICIs therapy. .