Haslam, A. & Prasad, V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Network Open 2, e192535 (2019).
Martins, F. et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat. Rev. Clin. Oncol. 16, 563â580 (2019).
Mahmood, S. S. et al. Myocarditis in patients treated with immune checkpoint inhibitors. J. Am. Coll. Cardiol. 71, 1755â1764 (2018).
Herrmann, J. et al. Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur. Heart J. 43, 280â299 (2022).
Bonaca, M. P. et al. Myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology. Circulation 140, 80â91 (2019).
Tawbi, H. A. et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N. Engl. J. Med. 386, 24â34 (2022).
Wang, D. Y. et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 4, 1721â1728 (2018).
Zhang, L. et al. Cardiotoxicity of immune checkpoint inhibitors. Curr. Treat. Options Cardiovasc. Med. 21, 32 (2019).
Salem, J.-E. et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. https://doi.org/10.1016/s1470-2045(18)30608-9 (2018).
Johnson, D. B. et al. Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med. 375, 1749â1755 (2016).
Champion, S. N. & Stone, J. R. Immune checkpoint inhibitor associated myocarditis occurs in both high-grade and low-grade forms. Mod. Pathol. 33, 99â108 (2019). 2019 33:1.
Ma, P. et al. Expansion of pathogenic cardiac macrophages in immune checkpoint inhibitor myocarditis. Circulation 149, 48â66 (2024).
Siddiqui, B. A. et al. Molecular pathways and cellular subsets associated with adverse clinical outcomes in overlapping immune-related myocarditis and myositis. Cancer Immunol. Res. 12, 964â987 (2024).
Finke, D. et al. Comparative transcriptomics of immune checkpoint inhibitor myocarditis identifies guanylate binding protein 5 and 6 dysregulation. Cancers 13, 2498 (2021).
Zhu, H. et al. Identification of pathogenic immune cell subsets associated with checkpoint inhibitor-induced myocarditis. Circulation 146, 316â335 (2022).
Axelrod, M. L. et al. T cells specific for α-myosin drive immunotherapy-related myocarditis. Nature 611, 818â826 (2022).
Wei, S. C. et al. A genetic mouse model recapitulates immune checkpoint inhibitor-associated myocarditis and supports a mechanism-based therapeutic intervention. Cancer Discov. 11, 614â625 (2021).
LitviÅuková, M. et al. Cells of the adult human heart. Nature 588, 466â472 (2020).
Liu, B., Zhang, Y., Wang, D., Hu, X. & Zhang, Z. Single-cell meta-analyses reveal responses of tumor-reactive CXCL13+ T cells to immune-checkpoint blockade. Nat. Cancer 3, 1123â1136 (2022).
van Eijs, M. J. M. et al. Toxicity-specific peripheral blood T and B cell dynamics in anti-PD-1 and combined immune checkpoint inhibition. Cancer Immunol. Immunother. 72, 4049â4064 (2023).
Auger, J.-P. et al. Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids. Nature 629, 184â192 (2024).
Lehmann, L. H. et al. Cardiomuscular biomarkers in the diagnosis and prognostication of immune checkpoint inhibitor myocarditis. Circulation 148, 473â486 (2023).
Stoeckius, M. et al. Simultaneous epitope and transcriptome measurement in single cells. Nat. Methods 14, 865â868 (2017).
Herndler-Brandstetter, D. et al. KLRG1+ effector CD8+ T cells lose KLRG1, differentiate into all memory T cell lineages, and convey enhanced protective immunity. Immunity 48, 716â729.e8 (2018).
Slack, R. J., Macdonald, S. J. F., Roper, J. A., Jenkins, R. G. & Hatley, R. J. D. Emerging therapeutic opportunities for integrin inhibitors. Nat. Rev. Drug Discov. 21, 60â78 (2022).
Simoni, Y. et al. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557, 575â579 (2018).
Zhang, J. et al. Compartmental analysis of T-cell clonal dynamics as a function of pathologic response to neoadjuvant PD-1 blockade in resectable non-small cell lung cancer. Clin. Cancer Res. 26, 1327â1337 (2020).
Ngwenyama, N. et al. CXCR3 regulates CD4+ T cell cardiotropism in pressure overload-induced cardiac dysfunction. JCI Insight 4, e125527 (2019).
Lv, H. J. et al. Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans. J. Clin. Invest. 121, 1561 (2011).
BÅyszczuk, P. Myocarditis in humans and in experimental animal models. Front. Cardiovasc. Med. 6, 64 (2019).
Kaya, Z., Katus, H. A. & Rose, N. R. Cardiac troponins and autoimmunity: their role in the pathogenesis of myocarditis and of heart failure. Clin. Immunol. 134, 80â88 (2010).
Sansonetti, M., Waleczek, F. J. G., Jung, M., Thum, T. & Perbellini, F. Resident cardiac macrophages: crucial modulators of cardiac (patho)physiology. Basic Res. Cardiol. https://doi.org/10.1007/s00395-020-00836-6 (2020).
Dick, S. A. et al. Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction. Nat. Immunol. 20, 29â39 (2019).
Dick, S. A. et al. Three tissue resident macrophage subsets coexist across organs with conserved origins and life cycles. Sci. Immunol. 7, eabf7777 (2022).
Umbarawan, Y. et al. FABP5 is a sensitive marker for lipid-rich macrophages in the luminal side of atherosclerotic lesions. Int. Heart J. 62, 666â676 (2021).
Lin, L.-Y. et al. Systems genetics approach to biomarker discovery: GPNMB and heart failure in mice and humans. G3 8, 3499â3506 (2018).
Xuan, Y., Chen, C., Wen, Z. & Wang, D. W. The roles of cardiac fibroblasts and endothelial cells in myocarditis. Front. Cardiovasc. Med. 9, 882027 (2022).
Alex, L. & Frangogiannis, N. G. Pericytes in the infarcted heart. Vasc. Biol. 1, H23âH31 (2019).
Chaffin, M. et al. Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy. Nature 608, 174â180 (2022).
Korsunsky, I. et al. Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med 3, 481â518.e14 (2022).
Kong, D. et al. The dynamic cellular landscape of grafts with acute rejection after heart transplantation. J. Heart Lung Transplant. 42, 160â172 (2023).
Luoma, A. M. et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell 182, 655â671.e22 (2020).
Thomas, M. F. et al. Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis. Nat. Med. 30, 1349â1362 (2024).
Kim, S. T. et al. Distinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy. Nat. Commun. 13, 1970 (2022).
Ji, C. et al. Myocarditis in cynomolgus monkeys following treatment with immune checkpoint inhibitors. Clin. Cancer Res. 25, 4735â4748 (2019).
Boughdad, S. et al. Ga-DOTATOC PET/CT to detect immune checkpoint inhibitor-related myocarditis. J. Immunother. Cancer 9, 3594 (2021).
Singh, S. et al. Tertiary lymphoid structure signatures are associated with immune checkpoint inhibitor related acute interstitial nephritis. JCI Insight https://doi.org/10.1172/jci.insight.165108 (2022).
Christen, U. et al. Combination treatment of a novel CXCR3 antagonist ACT-777991 with an anti-CD3 antibody synergistically increases persistent remission in experimental models of type 1 diabetes. Clin. Exp. Immunol. 214, 131â143 (2023).
Huang, Y. V. et al. A novel therapeutic approach using CXCR3 blockade to treat immune checkpoint inhibitor-mediated myocarditis. Preprint at bioRxiv https://doi.org/10.1101/2024.01.30.576279 (2024).
Chow, M. T. et al. Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti-PD-1 therapy. Immunity 50, 1498â1512.e5 (2019).
Zou, F. et al. Efficacy and safety of vedolizumab and infliximab treatment for immune-mediated diarrhea and colitis in patients with cancer: a two-center observational study. J. Immunother. Cancer 9, e003277 (2021).
Cautela, J. et al. Intensified immunosuppressive therapy in patients with immune checkpoint inhibitor-induced myocarditis. J. Immunother. Cancer 8, e001887 (2020).
Palaskas, N., Lopez-Mattei, J., Durand, J. B., Iliescu, C. & Deswal, A. Immune checkpoint inhibitor myocarditis: pathophysiological characteristics, diagnosis, and treatment. J. Am. Heart Assoc. 9, e013757 (2020).
Zhang, L. et al. Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis. Eur. Heart J. 41, 1733â1743 (2020).
Friedrich, M. G. et al. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J. Am. Coll. Cardiol. 53, 1475â1487 (2009).
Tucker, N. R. et al. Transcriptional and cellular diversity of the human heart. Circulation 142, 466â482 (2020).
Aretz, H. T. et al. Myocarditis. A histopathologic definition and classification. Am. J. Cardiovasc. Pathol. 1, 3â14 (1987).
Zheng, G. X. Y. et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 8, 14049 (2017).
Li, B. et al. Cumulus provides cloud-based data analysis for large-scale single-cell and single-nucleus RNA-seq. Nat. Methods 17, 793â798 (2020).
Gaublomme, J. T. et al. Nuclei multiplexing with barcoded antibodies for single-nucleus genomics. Nat. Commun. 10, 2907 (2019).
Villani, A. C. et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science 356, eaah4573 (2017).
Huang, X. & Huang, Y. Cellsnp-lite: an efficient tool for genotyping single cells. Bioinformatics 37, 4569â4571 (2021).
Heaton, H. et al. Souporcell: robust clustering of single-cell RNA-seq data by genotype without reference genotypes. Nat. Methods 17, 615â620 (2020).
Huang, Y., McCarthy, D. J. & Stegle, O. Vireo: Bayesian demultiplexing of pooled single-cell RNA-seq data without genotype reference. Genome Biol. 20, 273 (2019).
Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289â1296 (2019).
Batson, J., Royer, L. & Webber, J. Molecular cross-validation for single-cell RNA-seq. Preprint at bioRxiv https://doi.org/10.1101/786269 (2019).
Lun, A. T. L., Bach, K. & Marioni, J. C. Pooling across cells to normalize single-cell RNA sequencing data with many zero counts. Genome Biol. 17, 75 (2016).
Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).
Fonseka, C. Y. et al. Mixed-effects association of single cells identifies an expanded effectorCD4+ T cell subset in rheumatoid arthritis. Sci. Transl. Med. 463, eaaq0305 (2018).
Sherwood, A. M. et al. Deep sequencing of the human TCRγ and TCRβ repertoires suggests that TCRβ rearranges after αβ and γδ T cell commitment. Sci. Transl. Med. 3, 90ra61 (2011).
Cottrell, T. et al. Evaluating T-cell cross-reactivity between tumors and immune-related adverse events with TCR sequencing: pitfalls in interpretations of functional relevance. J. Immunother. Cancer 9, e002642 (2021).
Gupta, N. T. et al. Change-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data. Bioinformatics 31, 3356â3358 (2015).
Glanville, J. et al. Identifying specificity groups in the T cell receptor repertoire. Nature 547, 94â98 (2017).
Huang, H., Wang, C., Rubelt, F., Scriba, T. J. & Davis, M. M. Analyzing the Mycobacterium tuberculosis immune response by T-cell receptor clustering with GLIPH2 and genome-wide antigen screening. Nat. Biotechnol. 38, 1194â1202 (2020).
Oliveira, G. et al. Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma. Nature 596, 119â125 (2021).
Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234â239 (2019).
Cohen, C. J. et al. Enhanced antitumor activity of T cells engineered to express T-cell receptors with a second disulfide bond. Cancer Res. 67, 3898â3903 (2007).
Haga-Friedman, A., Horovitz-Fried, M. & Cohen, C. J. Incorporation of transmembrane hydrophobic mutations in the TCR enhance its surface expression and T cell functional avidity. J. Immunol. 188, 5538â5546 (2012).
Abelin, J. G. et al. Mass spectrometry profiling of HLA-associated peptidomes in mono-allelic cells enables more accurate epitope prediction. Immunity 46, 315â326 (2017).
nealpsmith, swemeshy & ikernin. villani-lab/myocarditis: Publication code release (v1.0.0). Zenodo https://doi.org/10.5281/zenodo.11519193 (2024).
Slowikowski, K. cellguide: Navigate single-cell RNA-seq datasets in your web browser (v0.01). Zenodo https://doi.org/10.5281/zenodo.8144195 (2023).
