An Immune Checkpoint Inhibitor Heart: How CD45RA + Effector Memory CD8 + T Cells (Temra) Are Implicated in Immune Checkpoint Inhibitor Myocarditis

HomeCirculationVol. 146, No. 4An Immune Checkpoint Inhibitor Heart: How CD45RA+ Effector Memory CD8+ T Cells (Temra) Are Implicated in Immune Checkpoint Inhibitor Myocarditis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAn Immune Checkpoint Inhibitor Heart: How CD45RA+ Effector Memory CD8+ T Cells (Temra) Are Implicated in Immune Checkpoint Inhibitor Myocarditis Marinos Kallikourdis, PhD and Gianluigi Condorelli, MD, PhD Marinos KallikourdisMarinos Kallikourdis Correspondence to: Marinos Kallikourdis, PhD, Via Manzoni 56, Rozzano 20089, Milan, Italy, Email E-mail Address: [email protected] https://orcid.org/0000-0001-9318-3368 Humanitas University, Pieve Emanuele, Italy (M.K., G.C.). Adaptive Immunity Laboratory (M.K.), Humanitas Research Hospital IRCCS, Rozzano, Italy. Search for more papers by this author and Gianluigi CondorelliGianluigi Condorelli Correspondence to: Gianluigi Condorelli, MD, PhD, Via Manzoni 56, Rozzano 20089, Milan, Italy, Email E-mail Address: [email protected] https://orcid.org/0000-0003-0481-6843 Humanitas University, Pieve Emanuele, Italy (M.K., G.C.). Cardio Center (G.C.), Humanitas Research Hospital IRCCS, Rozzano, Italy. Search for more papers by this author Originally published25 Jul 2022https://doi.org/10.1161/CIRCULATIONAHA.122.060788Circulation. 2022;146:336–338This article is a commentary on the followingIdentification of Pathogenic Immune Cell Subsets Associated With Checkpoint Inhibitor–Induced MyocarditisImmune checkpoint inhibitor (ICI) therapy for tumors is a life-saving treatment, yet occasionally patients experience ICI-induced myocarditis, an immune-mediated adverse reaction that is frequently lethal. The first in-depth report of ICI myocarditis in 2016 demonstrated that this fulminant myocarditis, initially identified in 2 patients receiving combined ICI treatment with anti–PD-1 and anti–CTLA-4, featured infiltration of the myocardium by T cells.1 This suggested an immune involvement in the pathogenesis of the disease. This hypothesis was very reasonable, given that ICIs act by releasing the brakes that keep already activated T cells from attacking their target. Hopefully, but not necessarily, their target includes antigens expressed by the tumor, but it could include antigens expressed in the heart. The same study performed analysis of the receptors with which T cells recognize the antigens that trigger them, the T-cell receptors, finding clonal expansions among the T cells in ICI myocarditis,1 a clear sign of antigen-driven activation and proliferation.Article, see p 316Many subsequent clinical studies have now clarified that the incidence of ICI myocarditis stands at a little higher than 1% of ICI treatments.2 Although this percentage is not large, the ubiquitous, and essential, use of ICIs means that many oncological patients may end up with ICI myocarditis. Studies of wild-type mice treated with mouse anti–PD-1 show small but significant losses of cardiac function,3,4 suggesting that the underlying mechanism of cardiac damage may be a more general phenomenon, not restricted to exceptional systemic preconditions.Efforts to decipher the mechanism of pathogenesis of ICI myocarditis have gathered pace; the most likely culprit is proinflammatory T cells expressing ICI ligands, such as PD-1. ICI treatment would release them to attack whatever antigen they react to, including those expressed in the heart. Supporting this, mouse model work has demonstrated that the disease is dependent on the presence of CD8+ T cells.4,5 In addition, the expression of PD-L1 on myocardial tissue1,4,6 suggests that the PD-1/PDL-1 axis may have a tolerance-promoting role in the heart, disrupted by ICI. Last, the finding of PD-1 expression on a cardiac cell subset likely to include peripheral regulatory T cells3 may also provide an additional means through which anti–PD-1 could break immune tolerance in the heart.Still, although mouse models, more accurate versions of which are being continuously developed,7 are essential for gaining mechanistic insight, there is a dire need for detailed analysis of large numbers of patients who have ICI myocarditis to better define the disease and to guarantee the clinical relevance of the mechanistic insight gained and therapeutic potential promised by ongoing studies.In this issue, Zhu et al8 apply a series of cutting-edge immunoprofiling tools, so far used mostly in advanced immuno-oncology studies, to the characterization of the peripheral blood immune cells, including CD8+ cytotoxic T cells, in ICI myocarditis. This deep-dive, applied to patients with ICI myocarditis (n=8), pushes the boundaries of our detailed understanding of the disease. The study has additional value as a resource because of the well-thought controls: healthy subjects, patients who have ICI with no adverse effects, but also, and this is indeed insightful, patients who have ICI with adverse effects that are not linked to myocarditis. Such a 4-way differential analysis may indeed yield biomarkers and molecular immune features, as well, that can initiate further mechanistic studies on the disease. The authors performed cytometry by time of flight, a more reliable form of cytometry based on labeling with isotopes measured by mass spectrometry, and single-cell sequencing and T-cell receptor sequencing, as well. This was performed on peripheral blood, which is the tissue most accessible, and thus most pragmatically relevant, to clinicians in an oncology ward; yet, it is important to note that they validated their data in the heart by using a mouse model of ICI myocarditis as a proxy.Their findings show a clear differential expansion, in ICI myocarditis, of a population of CD45RA+ reexpressing effector memory CD8+ T cells (Temra), confirmed by both cytometry by time of flight and RNA sequencing.8 These same cells convincingly showed the most clonal expansion, examined through single-cell T-cell receptor sequencing, signifying that they are undergoing antigen-driven activation and expansion during ICI myocarditis. A myocarditis-associated cluster of these cells highly expressed chemokine receptor CXCR38; this receptor would be expected to guide the cells from the peripheral blood (where they were sampled) to sites of high inflammatory activity, such as an inflamed heart.9 The authors also found compatible changes in a mouse model of ICI myocarditis, where cardiac effector memory CD8+ cells were both significantly increased and showed clonal expansion of their T-cell receptors.8 In other words, Zhu et al have characterized in detail the immune subpopulation that appears to respond the most during ICI myocarditis.What are the consequences for therapy development? The current standard therapy is immunosuppression by corticosteroids.10 A more nuanced solution was recently attempted by using T-cell immunomodulator abatacept (CTLA-4-Ig, which has the converse function compared with ICI anti–CTLA-4). Abatacept was successfully used in human patients with ICI myocarditis 11 and in a mouse model.7 As a solution that targets T cells, this is far more precise than other present alternatives. However, because potentially all T-cell activity will be dampened, theoretically this treatment may also affect any ongoing antitumoral T-cell activity. Thus, there is scope for even more golden bullet–like solutions, aiming for targets that will act differentially on the tumor versus the heart, attacking the former and sparing the latter.Immune responses involve soluble cytokines that affect almost all immune cell types. Michel et al4 showed that blockade of proinflammatory cytokine tumor necrosis factor together with anti–PD-1 attacks the tumor but spares the heart in a mouse model. Yet this is problematic in humans, because previous trials using anti–tumor necrosis factor in cardiac conditions yielded negative results.12 The use of tumor necrosis factor blockade in ICI myocarditis has been linked to further cardiovascular damage.10A subset of cytokines are chemokines, soluble molecules used by immune cells for homing, retention, and even costimulation.13 Zhu et al8 find unique chemokines and chemokine receptors in ICI myocarditis; this is in agreement with previous studies finding heart-specific chemotactic molecules.14 As the authors point out, inhibitors for chemokines already exist, and a new avenue of investigation may thus be opening.A better differentiator of responses are the antigens that drive the T cells. Cardiac antigens will, in their majority, be different from tumor antigens. However, we will need to discover these antigens. Alpha myosin (MYH6, also known as MYHCA) was recently shown to be of relevance for patients with ICI myocarditis.5 This may pave the way to more refined, antigen-specific T-cell solutions, such as engineered myosin-specific immunosuppressive chimeric antigen receptor–regulatory T cells, which could protect the heart while enabling other T cells to attack the tumor.The authors’ main finding is the identification of Temra cells as the main subpopulation clonally expanding in disease.8 Although Temra are potentially reactive against tumors, they are more likely to be found in the blood and are a minority among tumor-infiltrating T cells.15 Could tumor immunotherapy work without CD8+ Temra, sparing the heart from the subpopulation that the authors show is most associated with myocarditis? Further experimentation will surely tell.ICI myocarditis is an urgent clinical problem, both for the patients experiencing the cardiac symptoms, and for the oncological patients, as well, whose access to novel ICIs may be experiencing delays linked to slower drug development that has to keep ICI myocarditis in mind. Yet insightful analyses, such as the one in this issue by Zhu et al, and the many innovative therapies attempted in mouse models and human patients, as well, afford good reason to be optimistic.Article InformationSources of FundingThis work was supported by grant AIRC IG24988.Disclosures None.FootnotesCirculation is available at www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 338.Correspondence to: Marinos Kallikourdis, PhD, Via Manzoni 56, Rozzano 20089, Milan, Italy, Email marinos.[email protected]itCorrespondence to: Gianluigi Condorelli, MD, PhD, Via Manzoni 56, Rozzano 20089, Milan, Italy, Email gianluigi.[email protected]euReferences1. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, Puzanov I, Alexander MR, Bloomer TL, et al. 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Circulation. 2022;146:316-335 July 26, 2022Vol 146, Issue 4 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.060788PMID: 35877835 Originally publishedJuly 25, 2022 KeywordsmyocarditisEditorialsimmune checkpoint inhibitorsCD8-positive T-lymphocyteschemokinesimmunotherapyPDF download Advertisement SubjectsCardiotoxicityGrowth Factors/CytokinesInflammationInflammatory Heart DiseaseMyocardial Biology