Immune responses in checkpoint myocarditis across heart, blood and tumour

Steven M Blum; Daniel A Zlotoff; Neal P Smith; Isabela J Kernin; Swetha Ramesh; Leyre Zubiri; Joshua Caplin; Nandini Samanta; Sidney Martin; Mike Wang; Alice Tirard; Yuhui Song; Katherine H Xu; Jaimie Barth; Pritha Sen; Kamil Slowikowski; Jessica Tantivit; Kasidet Manakongtreecheep; Benjamin Y Arnold; Mazen Nasrallah; Christopher J Pinto; Daniel McLoughlin; Monica Jackson; PuiYee Chan; Aleigha Lawless; William A Michaud; Tatyana Sharova; Linda T Nieman; Justin F Gainor; Catherine J Wu; Dejan Juric; Mari Mino-Kenudson; Giacomo Oliveira; Ryan J Sullivan; Genevieve M Boland; James R Stone; Molly F Thomas; Tomas G Neilan; Kerry L Reynolds; Alexandra-Chloé Villani

doi:10.1038/s41586-024-08105-5

Immune responses in checkpoint myocarditis across heart, blood and tumour

Nature. 2024 Nov 6. doi: 10.1038/s41586-024-08105-5. Online ahead of print.

Authors

Steven M Blum^#^{1

2

3

4

5}, Daniel A Zlotoff^#^{1

3

4

5

6}, Neal P Smith^#^{1

3

5}, Isabela J Kernin^#^{1

3

5}, Swetha Ramesh^#^{1

3

5}, Leyre Zubiri^{1

2

3

5}, Joshua Caplin⁶, Nandini Samanta^{1

3

5}, Sidney Martin^{1

3

5}, Mike Wang², Alice Tirard^{1

3

5}, Yuhui Song⁵, Katherine H Xu⁵, Jaimie Barth⁷, Pritha Sen^{1

3

4

5

8

9

10}, Kamil Slowikowski^{1

3

4

5}, Jessica Tantivit^{1

3

5}, Kasidet Manakongtreecheep^{1

3

5}, Benjamin Y Arnold^{1

3

5}, Mazen Nasrallah^{1

3

4

5

10}, Christopher J Pinto^{2

11}, Daniel McLoughlin^{2

11}, Monica Jackson^{2

11}, PuiYee Chan^{2

11}, Aleigha Lawless^{5

12}, William A Michaud^{5

12}, Tatyana Sharova^{5

12}, Linda T Nieman^{4

5}, Justin F Gainor^{2

4}, Catherine J Wu^{3

4

13

9}, Dejan Juric^{2

3

4}, Mari Mino-Kenudson^{4

7}, Giacomo Oliveira^{3

4

13}, Ryan J Sullivan^{2

4}, Genevieve M Boland^{3

4

5

12}, James R Stone^{4

7}, Molly F Thomas^{1

3

4

5

14

15

16}, Tomas G Neilan^{4

6}, Kerry L Reynolds^{2

4}, Alexandra-Chloé Villani^{17

18

19

20}

Affiliations

¹ Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
² Mass General Cancer Center, Boston, MA, USA.
³ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
⁴ Harvard Medical School, Boston, MA, USA.
⁵ Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁶ Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁸ Transplant, Oncology and Immunocompromised Host Program, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA.
⁹ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Division of Rheumatology, North Shore Physicians Group, Department of Medicine, Mass General Brigham Healthcare Center, Lynn, MA, USA.
¹¹ Clinical Research Center, Massachusetts General Hospital, Boston, MA, USA.
¹² Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
¹³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁴ Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Division of Gastroenterology, Department of Medicine, Oregon Health and Sciences University, Portland, OR, USA.
¹⁶ Department of Cell, Developmental, and Cancer Biology, Oregon Health and Sciences University, Portland, OR, USA.
¹⁷ Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected].
¹⁸ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. [email protected].
¹⁹ Harvard Medical School, Boston, MA, USA. [email protected].
²⁰ Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected].

^# Contributed equally.

PMID: 39506125
DOI: 10.1038/s41586-024-08105-5

Abstract

Immune checkpoint inhibitors are widely used anticancer therapies¹ that can cause morbid and potentially fatal immune-related adverse events such as immune-related myocarditis (irMyocarditis)^2-5. The pathogenesis of irMyocarditis and its relationship to antitumour immunity remain poorly understood. Here we sought to define immune responses in heart, tumour and blood in patients with irMyocarditis by leveraging single-cell RNA sequencing coupled with T cell receptor (TCR) sequencing, microscopy and proteomics analyses of samples from 28 patients with irMyocarditis and 41 unaffected individuals. Analyses of 84,576 cardiac cells by single-cell RNA sequencing combined with multiplexed microscopy demonstrated increased frequencies and co-localization of cytotoxic T cells, conventional dendritic cells and inflammatory fibroblasts in irMyocarditis heart tissue. Analyses of 366,066 blood cells revealed decreased frequencies of plasmacytoid dendritic cells, conventional dendritic cells and B lineage cells but an increased frequency of other mononuclear phagocytes in irMyocarditis. Fifty-two heart-expanded TCR clones from eight patients did not recognize the putative cardiac autoantigens α-myosin, troponin I or troponin T. Additionally, TCRs enriched in heart tissue were largely nonoverlapping with those enriched in paired tumour tissue. The presence of heart-expanded TCRs in a cycling blood CD8 T cell population was associated with fatal irMyocarditis case status. Collectively, these findings highlight crucial biology driving irMyocarditis and identify putative biomarkers.