Molecular Pathology of Immune Checkpoint Inhibitor-Induced Myocarditis
DOI:
https://doi.org/10.30683/1927-7229.2020.09.04Keywords:
Autoimmunity, CD4 T cells, CTLA-4, CTLs, Immune checkpoint inhibitor, Myocarditis, PD-1.Abstract
The improvement in tumor outcomes associated with the use of immune checkpoint inhibitors (ICIs) is supported by results of numerous clinical trials. Even though most publications reporting the clinical efficacy of these agents include a discussion of the biological mechanisms, narratives related to the complex nature of the adaptive immune response are frequently, though they should not be, mundane. It is also apparent that there tends to be a cursory, or even complete absence, of explanations related to the pathological mechanism(s) of the toxic reactions in the vast majority of papers that report adverse events associated with ICI therapy. Furthermore, the belief that cytotoxic CD8+ T cells mediate not only the antitumor, but also immune-related adverse, effects may be plausible, yet incorrect. This being the case, instead of providing only clinical details of a severe adverse event associated with combination ICI therapy in a patient with melanoma, the authors chose to scrutinize the repertoire and role of T cells in the pathogenesis of myocarditis as an example of other ICI-associated incidents of autoimmunity.
References
Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19(1): 683-765. https://doi.org/10.1146/annurev.immunol.19.1.683 DOI: https://doi.org/10.1146/annurev.immunol.19.1.683
Joss A, Akdis M, Faith A, Blaser KA, Akdis CA. IL-10 directly acts on T cells by specifically altering the CD28 co-stimulation pathway. Eur J Immunol 2000; 30(6): 1683-90. https://doi.org/10.1002/1521-4141(200006)30:6<1683::AID-IMMU1683>3.0.CO;2-A DOI: https://doi.org/10.1002/1521-4141(200006)30:6<1683::AID-IMMU1683>3.0.CO;2-A
Park M-J, Lee S-H, Kim E-K, Lee E-J, Baek J-A, Park S-H, et al. Interleukin-10 produced by myeloid-derived suppressor cells is critical for the induction of Tregs and attenuation of rheumat oid inflammation in mice. Sci Rep 2018; 8: 3753. https://doi.org/10.1038/s41598-018-21856-2 DOI: https://doi.org/10.1038/s41598-018-21856-2
Wan YY, Flavell RA. Regulatory T cells, transforming growth factor-β, and immune suppression. Proc Am Thorac Soc 2007; 4(3): 271-6. https://doi.org/10.1513/pats.200701-020AW DOI: https://doi.org/10.1513/pats.200701-020AW
Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity 2015; 21; 42(4): 607-12. https://doi.org/10.1016/j.immuni.2015.04.005 DOI: https://doi.org/10.1016/j.immuni.2015.04.005
McDermott D, Haanen J, Chen T-T, Lorigan P, O'Day S, for the MDX010-20 investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol 2013; 24(10): 2694-8. https://doi.org/10.1093/annonc/mdt291 DOI: https://doi.org/10.1093/annonc/mdt291
Hodi, FS, Chiarion-Sileni V, Gonzalez R, Grob J-J, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (Check Mate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 2018; 19(11): 1480-92. https://doi.org/10.1016/S1470-2045(18)30700-9 DOI: https://doi.org/10.1016/S1470-2045(18)30700-9
Mok TSK, Wu Y-L, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomized, open-label, controlled, phase 3 trial. Lancet 2019; 393(10183): 1819-30. https://doi.org/10.1016/S0140-6736(18)32409-7 DOI: https://doi.org/10.1016/S0140-6736(18)32409-7
Rapoport BL, van Eeden R, Sibaud V, Epstein JB, Klastersky J, Aapro M, et al. Supportive care for patients undergoing immunotherapy. Supp Care Cancer 2017; 25(10): 3017-30. https://doi.org/10.1007/s00520-017-3802-9 DOI: https://doi.org/10.1007/s00520-017-3802-9
Hu YB, Zhang Q, Li HJ, Michot JM, Liu HB, Zhan P, et al. Evaluation of rare but severe immune related adverse effects in PD-1 and PD-L1 inhibitors in non-small cell lung cancer: a meta-analysis. Transl Lung Cancer Res 2017; 6(Suppl 1): S8-20. https://doi.org/10.21037/tlcr.2017.12.10 DOI: https://doi.org/10.21037/tlcr.2017.12.10
Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al. AJCC Cancer Staging Manual. 8th ed. New York: Springer 2017. https://doi.org/10.1007/978-3-319-40618-3 DOI: https://doi.org/10.1007/978-3-319-40618-3_2
Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018; 36(17): 1714-68. https://doi.org/10.1200/JCO.2017.77.6385 DOI: https://doi.org/10.1200/JCO.2017.77.6385
Palaskas N, Lopez-Mattei J, Durand JB, Iliescu C, Deswal A. Immune checkpoint inhibitor myocarditis: pathophysiological characteristics, diagnosis, and treatment. J Am Heart Assoc 2020; 9(2): e0137579. https://doi.org/10.1161/JAHA.119.013757 DOI: https://doi.org/10.1161/JAHA.119.013757
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373(1): 23-34. https://doi.org/10.1056/NEJMoa1504030 DOI: https://doi.org/10.1056/NEJMoa1504030
Wang DY, Salem JE, Cohen JV. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 2018; 4(12): 1721-8. https://doi.org/10.1001/jamaoncol.2018.3923 DOI: https://doi.org/10.1001/jamaoncol.2018.3923
Harper K, Balzano C, Rouvier E, Mattéi MG, Luciani MF, Golstein P. CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J Immunol 1991 Aug 1; 147(3): 1037-44.
Collins AV, Brodie DW, Gilbert RJ, Iaboni A, Manso-Sancho R, Walse B, et al. The interaction properties of costimulatory molecules revisited. Immunity 2002; 17(2): 201-10. https://doi.org/10.1016/S1074-7613(02)00362-X DOI: https://doi.org/10.1016/S1074-7613(02)00362-X
Lindsten T, Lee KP, Harris ES, Petryniak B, Craighead N, Reynolds PJ, et al. Characterization of CTLA-4 structure and expression on human T cells. J Immunol 1993; 151(7): 3489-99.
Linsley PS, Greene JL, Tan P, Bradshaw J, Ledbetter JA, Anasetti C, et al. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med 1992; 176(6): 1595-1604. https://doi.org/10.1084/jem.176.6.1595 DOI: https://doi.org/10.1084/jem.176.6.1595
Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994; 1(5): 405-13. https://doi.org/10.1016/1074-7613(94)90071-X DOI: https://doi.org/10.1016/1074-7613(94)90071-X
Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O’Shea MA, et al. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 2008; 181(10): 6738-46. https://doi.org/10.4049/jimmunol.181.10.6738 DOI: https://doi.org/10.4049/jimmunol.181.10.6738
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192(7): 1027-34. https://doi.org/10.1084/jem.192.7.1027 DOI: https://doi.org/10.1084/jem.192.7.1027
Lin DY, Tanaka Y, Iwasaki M, Gittis AG, Su HP, Mikami B, et al. The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc Natl Acad Sci U S A 2008; 105(8): 3011-6. https://doi.org/10.1073/pnas.0712278105 DOI: https://doi.org/10.1073/pnas.0712278105
Zinkernagel RM, Doherty PC. Immunological surveillance against altered self-components by sensitised T lymphocytes in lymphocytic choriomeningitis. Nature 1974; 251(5475): 547-8. https://doi.org/10.1038/251547a0 DOI: https://doi.org/10.1038/251547a0
Berner B, Akca D, Jung T, Muller GA, Reuss-Borst MA. Analysis of Th1 and Th2 cytokines expressing CD4+ and CD8+ T cells in rheumatoid arthritis by flow cytometry. J Rheumatol 2000; 27(5): 1128-35.
Wong F, Karttunen J, Dumont C, Wen L, Visintin I, Pilip I, et al. Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library. Nat Med 1999; 5(9): 1026-31. https://doi.org/10.1038/12465 DOI: https://doi.org/10.1038/12465
Rocken M, Saurat JH, Hauser C: A common precursor for CD4+ T cells producing IL-2 or IL-4. J Immunol 1992; 148(4): 1031-6.
Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 2015; 74(1): 5-17. https://doi.org/10.1016/j.cyto.2014.09.011 DOI: https://doi.org/10.1016/j.cyto.2014.09.011
Van Boxel JA, Paget SA. Predominantly T-cell infiltrate in rheumatoid synovial membranes. N Engl J Med 1975; 293(11): 517-20. https://doi.org/10.1056/NEJM197509112931101 DOI: https://doi.org/10.1056/NEJM197509112931101
Banerjee S, Webber C, Poole AR: The induction of arthritis in mice by the cartilage proteoglycan aggrecan: roles of CD4+ and CD8+ T cells. Cell Immunol 1992; 144(2): 347-57. https://doi.org/10.1016/0008-8749(92)90250-S DOI: https://doi.org/10.1016/0008-8749(92)90250-S
Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996; 383(6603): 787-93. https://doi.org/10.1038/383787a0 DOI: https://doi.org/10.1038/383787a0
Hassel JC, Heinzerling L, Aberle J, Bähr O, Eigentler TK, Grimm MO, et al. Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. Cancer Treat Rev 2017; 57: 36-49. https://doi.org/10.1016/j.ctrv.2017.05.003 DOI: https://doi.org/10.1016/j.ctrv.2017.05.003
Alegre ML, Shiels H, Thompson CB, Gajewski TF. Expression and function of CTLA-4 in Th1 and Th2 cells. J Immunol 1998; 161(7): 3347-56.
Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997; 389(6652): 737-42. https://doi.org/10.1038/39614 DOI: https://doi.org/10.1038/39614
Foussat A, Cottrez F, Brun V, Fournier N, Breittmayer J-P, Groux H. Comparative study between T regulatory type 1 and CD4+CD25+ T cells in the control of inflammation. J Immunol 2003; 171(10): 5018-26. https://doi.org/10.4049/jimmunol.171.10.5018 DOI: https://doi.org/10.4049/jimmunol.171.10.5018
Kalekar LA, Mueller DL. Relationship between CD4 regulatory T cells and anergy in vivo. J Immunol 2017; 198(7): 2527-33. https://doi.org/10.4049/jimmunol.1602031 DOI: https://doi.org/10.4049/jimmunol.1602031
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155(3): 1151-64.
Fontenot, J. D., Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4(4): 330-6. https://doi.org/10.1038/ni904 DOI: https://doi.org/10.1038/ni904
Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendo-crinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27(1): 20-1. https://doi.org/10.1038/83713 DOI: https://doi.org/10.1038/83713
Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martinez-Llordella M, Ashby M, et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 2009; 10(9): 1000-7. https://doi.org/10.1038/ni.1774 DOI: https://doi.org/10.1038/ni.1774
Hori S, Takahashi T, Sakaguchi S. Control of autoimmunity by naturally arising regulatory CD4+ T cells. Adv Immunol 2003; 81: 331-71. https://doi.org/10.1016/S0065-2776(03)81008-8 DOI: https://doi.org/10.1016/S0065-2776(03)81008-8
Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192(2): 303-10. https://doi.org/10.1084/jem.192.2.303 DOI: https://doi.org/10.1084/jem.192.2.303
Schmidt EM, Wang CJ, Ryan GA, Clough LE Qureshi OS, Goodall M, et al. Ctla-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity. J Immunol 2009; 182(1): 274-82. https://doi.org/10.4049/jimmunol.182.1.274 DOI: https://doi.org/10.4049/jimmunol.182.1.274
Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, et al. A new member of the immunoglobulin superfamily--CTLA-4. Nature 1987; 328(6127): 267-70. https://doi.org/10.1038/328267a0 DOI: https://doi.org/10.1038/328267a0
Chan DV, Gibson HM, Aufiero BM, Wilson AJ, Hafner MS, Mi Q-S, et al. Differential CTLA-4 expression in human CD4+ versus CD8+ T cells is associated with increased NFAT1 and inhibition of CD4+ proliferation. Genes Immun 2014; 15(1): 25-32. https://doi.org/10.1038/gene.2013.57 DOI: https://doi.org/10.1038/gene.2013.57
Gattinoni L, Ranganathan A, Surman DR, Palmer DC, Antony PA, Theoret MR, et al. CTLA-4 dysregulation of self/tumor-reactive CD8+ T-cell function is CD4+ T-cell dependent. Blood 2006; 108(12): 3818-23. https://doi.org/10.1182/blood-2006-07-034066 DOI: https://doi.org/10.1182/blood-2006-07-034066
Hinrichs CS, Spolski R, Paulos CM, Gattinoni L, Kerstann KW, Palmer DC, et al. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood 2008; 111(11): 5326-33. https://doi.org/10.1182/blood-2007-09-113050 DOI: https://doi.org/10.1182/blood-2007-09-113050
Malek TR, Castro I. Interleukin-2 receptor signaling: At the interface between tolerance and immunity. Immunity 2010; 33(2): 153-65. https://doi.org/10.1016/j.immuni.2010.08.004 DOI: https://doi.org/10.1016/j.immuni.2010.08.004
Krummel MF, Allison JP. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med 1996; 183(6): 2533-40. https://doi.org/10.1084/jem.183.6.2533 DOI: https://doi.org/10.1084/jem.183.6.2533
Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature 2006; 441(7095): 890-3. https://doi.org/10.1038/nature04790 DOI: https://doi.org/10.1038/nature04790
