⭐️NEW PAPER OUT in @Nature⭐️ 🫀What is the relationship between the immune responses in the heart, blood, and tumor in patients with inflammation in the heart resulting from cancer immunotherapy (irMyocarditis)? This 🧵 breaks down the key findings 1/n https://t.co/0Jdhrw63VX

Science Seminar with Dr. Villani on March 20th 2pm titled Learning the rules of human #immune tolerance through the lenses of single-cell #genomics. Please register at https://t.co/4OOM3eYfuK @villanilab @MGHMedicine @harvardmed @CavMedEd

We had the pleasure of hosting Dr. Chloe Villani @villanilab for the M&I Seminar Series today. We appreciated learning more about her research "Unraveling Immune Tolerance: Insights from Immune-Related Adverse Events in Immunotherapy". @UofUResearch @UofUHealth @UofUPathology

We are excited to announce the Quantum Award recipients! The team will explore potentially life-threatening complications that can accompany even the most successful cancer immunotherapies, seeking to separate the benefit from side effects. https://t.co/x7UGrNb1x2

We’re excited to see our paper published in @Nature! Congrats to a fantastic team in the @villanilab and the @MGHCancerCenter! I’d like to especially thank the patients and their families for participating in our effort. We are all tremendously grateful for their generosity.

🎉 CONGRATULATIONS TEAM 🎉 👏 Incredible effort by our brilliant team - special kudos to @sm_blum, @DZlotoff, #Neal, #Isabela, and #Swetha. 🔗 Go check out the fantastic tweetorial they have prepared to break down the key findings of our new study:

🤝 Huge thanks to our incredible collaborators across @vilanilab @kreynoldsMD @TomasNeilan @Boland_Lab and beyond for making this possible! We hope this 🧵 sparked your curiosity! Dive into the full study for deeper insights and findings. Questions? Let’s connect! 💬 12/12

🙏🏻 We are grateful to all donors and their families; the @MGHCancerCenter; the Ellison 16 staff; the MGH cardiac catheterization laboratory; and the MGH Severe Immunotherapy Complications Service @MGH_RI @mghcvrc @MGHMedicine @harvardmed @broadinstitute @MGHHeartHealth 11/n

We 👉 Identify novel biomarkers of irMyocarditis onset and severity. 👉 Implicate non-immune cells in pathogenesis. 👉 Suggest that Tcell responses in the heart are distinct from those in tumors. We hope that our findings will help to develop strategies to mitigate irMyocarditis

🌟 Inflammatory fibroblasts 🔍 Cardiac damage (serum troponin T) correlates with CXCL9-expressing fibroblast abundance and gene programs associated with viral myocarditis and interferon responses. 👉 Fibroblasts populations may represent novel mediators of irMyocarditis. 9/n

🌟 cDCs in the heart 🔍 cDCs are increased in the hearts of irMyocarditis patients and their intracardiac frequency correlates with serum troponin T levels. 👉 These results highlight the importance of infiltrating antigen presenting cells in the inflamed heart. 8/n

🌟 Antigens in irMyocarditis 🔍 None of the 52 most expanded TCRs from across 8 irMyocarditis patients responded to the heart proteins α-myosin, troponin I, or T. 👉 This suggests that the most expanded intracardiac T cell clones recognize novel autoantigen(s). 7/n

🌟 TCR clonality heart-blood 🔍 Shared clones are enriched in circulating cycling CXCR3+ CD8 T cells, which are correlated with fatality. 👉 Circulating cycling CXCR3+ CD8 T cells may act as a pathologic cellular mediator and serve as a biomarker of severity in irMyocarditis.

🌟 TCR clonality heart-tumor 🔍 Expanded heart clones ≠ expanded tumor clones 👉 Distinct T-cell clones suggest that T-cell responses in these patients may be directed against distinct antigens, providing hope to disentangle irMyocarditis from anti-tumor responses. 5/n

🌟 Gene expression changes in intracardiac T cells 🔍 T-cell proliferation and mTOR signaling gene sets correlated with cardiac damage (serum troponin T levels). 👉 The degree of irMyocarditis severity correlates with gene expression patterns in the microenvironment. 4/n

🌟 Cell frequency changes in irMyocarditis 🫀 In heart: ⬆️ CD8 and CD4 T cells, conventional dendritic cells (cDCs), inflammatory fibroblasts, cancer cells (?!) 🩸 In blood: ⬆️ Monocytes ⬇️ Plasmacytoid dendritic cells (pDCs), cDCs, B cells and CD4 T cells 3/n

We analyzed samples from 69 individuals: 👥 28 patients with irMyocarditis 👥 41 unaffected individuals and profiled: 🩸 Blood 💧 Serum 🫀 Heart ⚠️ Tumor using: 🔍scRNA-seq + TCR-seq 🔍Cell surface protein profiling 🔍Serum factor analysis 🔍Bulk TCR-β-seq 🔬Microscopy 2/n

Congratulations, Doctor @saguilarfer for the EXCELLENT thesis defence today @cnag_eu 🥳 Your current and future team mates @hoheyn lab and @villanilab are very proud of you! 🤩

🔬By bridging clinical care and research, we aspire to improve and advance patient care and outcomes. 📢Follow us for the latest news and breakthroughs in this exciting field.

🧪We are also dedicated to defining the underpinnings of a range of human immune disorders through our systems immunology approach. 🚀Our groundwork is paving the way for developing a human immune lexicon that is key to promote effective bench-to-bedside translation of findings.