Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives

Nature Reviews Neurology volume 13, pages 755–763 (2017)Cite this article

Subjects

Abstract

Cancer treatment strategies based on immune stimulation have recently entered the clinical arena, with unprecedented success. Immune checkpoint inhibitors (ICIs) work by indiscriminately promoting immune responses, which target tumour-associated antigens or tumour-specific mutations. However, the augmented immune response, most notably the T cell response, can cause either direct neurotoxicity or, more commonly, indirect neurotoxic effects through systemic or local inflammatory mechanisms or autoimmune mechanisms. Consequently, patients treated with ICIs are susceptible to CNS disease, including paraneoplastic neurological syndromes, encephalitis, multiple sclerosis and hypophysitis. In this Opinion article, we introduce the mechanisms of action of ICIs and review their adverse effects on the CNS. We highlight the importance of early detection of these neurotoxic effects, which should be distinguished from brain metastasis, and the need for early detection of neurotoxicity. It is crucial that physicians are well informed of these neurological adverse effects, given the anticipated increase in the use of immunotherapies to treat cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Immune inhibitory receptors that regulate T cell function.
Figure 2: Co-stimulatory receptors as immunomodulatory targets.

Similar content being viewed by others

References

  1. Boutros, C. et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat. Rev. Clin. Oncol. 13, 473–486 (2016).

    Article  CAS  PubMed  Google Scholar 

  2. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Allison, J. P. Checkpoints. Cell 162, 1202–1205 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Tran, E., Robbins, P. F. & Rosenberg, S. A. 'Final common pathway' of human cancer immunotherapy: targeting random somatic mutations. Nat. Immunol. 18, 255–262 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen, L. & Flies, D. B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227–242 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Sharma, P. & Allison, J. P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Schadendorf, D. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ansell, S. M. et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372, 311–319 (2015).

    Article  PubMed  CAS  Google Scholar 

  16. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Fehrenbacher, L. et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387, 1837–1846 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Balar, A. V. et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389, 67–76 (2017).

    Article  CAS  PubMed  Google Scholar 

  19. Butte, M. J., Keir, M. E., Phamduy, T. B., Sharpe, A. H. & Freeman, G. J. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27, 111–122 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Anderson, A. C., Joller, N. & Kuchroo, V. K. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44, 989–1004 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nowak, E. C. et al. Immunoregulatory functions of VISTA. Immunol. Rev. 276, 66–79 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cuzzubbo, S. et al. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur. J. Cancer 73, 1–8 (2017).

    Article  CAS  PubMed  Google Scholar 

  24. Wick, W., Hertenstein, A. & Platten, M. Neurological sequelae of cancer immunotherapies and targeted therapies. Lancet Oncol. 17, e529–e541 (2016).

    Article  PubMed  Google Scholar 

  25. Hottinger, A. F. Neurologic complications of immune checkpoint inhibitors. Curr. Opin. Neurol. 29, 806–812 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Spain, L. et al. Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Ann. Oncol. 28, 377–385 (2017).

    Article  CAS  PubMed  Google Scholar 

  27. Gerdes, L. A. et al. CTLA4 as immunological checkpoint in the development of multiple sclerosis. Ann. Neurol. 80, 294–300 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Larkin, J. et al. Neurologic serious adverse events associated with nivolumab plus ipilimumab or nivolumab alone in advanced melanoma, including a case series of encephalitis. Oncologist 22, 709–718 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Williams, T. J. et al. Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer. JAMA Neurol. 73, 928–933 (2016).

    Article  PubMed  Google Scholar 

  30. Gettings, E. J., Hackett, C. T. & Scott, T. F. Severe relapse in a multiple sclerosis patient associated with ipilimumab treatment of melanoma. Mult. Scler. 21, 670 (2015).

    Article  PubMed  Google Scholar 

  31. Wilson, M. A. et al. Acute visual loss after ipilimumab treatment for metastatic melanoma. J. Immunother. Cancer 4, 66 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Wilgenhof, S. & Neyns, B. Anti-CTLA-4 antibody-induced Guillain–Barré syndrome in a melanoma patient. Ann. Oncol. 22, 991–993 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Liao, B., Shroff, S., Kamiya-Matsuoka, C. & Tummala, S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro Oncol. 16, 589–593 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bompaire, F. et al. Severe meningo-radiculo-neuritis associated with ipilimumab. Invest. New Drugs 30, 2407–2410 (2012).

    Article  PubMed  Google Scholar 

  35. Thaipisuttikul, I., Chapman, P. & Avila, E. K. Peripheral neuropathy associated with ipilimumab: a report of 2 cases. J. Immunother. 38, 77–79 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Loochtan, A. I., Nickolich, M. S. & Hobson-Webb, L. D. Myasthenia gravis associated with ipilimumab and nivolumab in the treatment of small cell lung cancer. Muscle Nerve 52, 307–308 (2015).

    Article  PubMed  Google Scholar 

  37. Cao, Y. et al. CNS demyelination and enhanced myelin-reactive responses after ipilimumab treatment. Neurology 86, 1553–1556 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Maurice, C. et al. Subacute CNS demyelination after treatment with nivolumab for melanoma. Cancer Immunol. Res. 3, 1299–1302 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Brown, M. P., Hissaria, P., Hsieh, A. H., Kneebone, C. & Vallat, W. Autoimmune limbic encephalitis with anti-contactin-associated protein-like 2 antibody secondary to pembrolizumab therapy. J. Neuroimmunol. 305, 16–18 (2017).

    Article  CAS  PubMed  Google Scholar 

  40. Bossart, S. et al. Case report: encephalitis, with brainstem involvement, following checkpoint inhibitor therapy in metastatic melanoma. Oncologist 22, 749–753 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Yshii, L. M. et al. CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model. Brain 139, 2923–2934 (2016).

    Article  PubMed  Google Scholar 

  42. Waisman, A., Liblau, R. S. & Becher, B. Innate and adaptive immune responses in the CNS. Lancet Neurol. 14, 945–955 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Salama, A. D. et al. Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J. Exp. Med. 198, 71–78 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rui, Y., Honjo, T. & Chikuma, S. Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response. Proc. Natl Acad. Sci. USA 110, 16073–16078 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kroner, A. et al. Accelerated course of experimental autoimmune encephalomyelitis in PD-1-deficient central nervous system myelin mutants. Am. J. Pathol. 174, 2290–2299 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jiang, T. T. et al. Programmed death-1 culls peripheral accumulation of high-affinity autoreactive CD4 T cells to protect against autoimmunity. Cell Rep. 17, 1783–1794 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Vincent, A., Lang, B. & Newsom-Davis, J. Autoimmunity to the voltage-gated calcium channel underlies the Lambert–Eaton myasthenic syndrome, a paraneoplastic disorder. Trends Neurosci. 12, 496–502 (1989).

    Article  CAS  PubMed  Google Scholar 

  48. Darnell, R. B. & Posner, J. B. Paraneoplastic syndromes involving the nervous system. N. Engl. J. Med. 349, 1543–1554 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Darnell, R. B. & Posner, J. B. Observing the invisible: successful tumor immunity in humans. Nat. Immunol. 4, 201 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Jaeckle, K. A. et al. Autoimmune response of patients with paraneoplastic cerebellar degeneration to a Purkinje cell cytoplasmic protein antigen. Ann. Neurol. 18, 592–600 (1985).

    Article  CAS  PubMed  Google Scholar 

  51. Dalmau, J., Furneaux, H. M., Gralla, R. J., Kris, M. G. & Posner, J. B. Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer — a quantitative western blot analysis. Ann. Neurol. 27, 544–552 (1990).

    Article  CAS  PubMed  Google Scholar 

  52. Pignolet, B. S., Gebauer, C. M. & Liblau, R. S. Immunopathogenesis of paraneoplastic neurological syndromes associated with anti-Hu antibodies: a beneficial antitumor immune response going awry. Oncoimmunology 2, e27384 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Steinman, L. Conflicting consequences of immunity to cancer versus autoimmunity to neurons: insights from paraneoplastic disease. Eur. J. Immunol. 44, 3201–3205 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Schneider, S., Potthast, S., Komminoth, P., Schwegler, G. & Bohm, S. PD-1 checkpoint inhibitor associated autoimmune encephalitis. Case Rep. Oncol. 10, 473–478 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Laubli, H. et al. Cerebral vasculitis mimicking intracranial metastatic progression of lung cancer during PD-1 blockade. J. Immunother. Cancer 5, 46 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Salam, S., Lavin, T. & Turan, A. Limbic encephalitis following immunotherapy against metastatic malignant melanoma. BMJ Case Rep. http://dx.doi.org/10.1136/bcr-2016-215012 (2016).

  57. Arriola, E. et al. Outcome and biomarker analysis from a multicenter phase 2 study of ipilimumab in combination with carboplatin and etoposide as first-line therapy for extensive-stage SCLC. J. Thorac. Oncol. 11, 1511–1521 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Antonia, S. J. et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 17, 883–895 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. Ben-Nun, A. et al. From classic to spontaneous and humanized models of multiple sclerosis: impact on understanding pathogenesis and drug development. J. Autoimmun. 54, 33–50 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Carter, L. L. et al. PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 182, 124–134 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Takizawa, S. et al. Role of the programmed death-1 (PD-1) pathway in regulation of Theiler's murine encephalomyelitis virus-induced demyelinating disease. J. Neuroimmunol. 274, 78–85 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Hohlfeld, R., Dornmair, K., Meinl, E. & Wekerle, H. The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets. Lancet Neurol. 15, 198–209 (2016).

    Article  CAS  PubMed  Google Scholar 

  63. Hohlfeld, R., Dornmair, K., Meinl, E. & Wekerle, H. The search for the target antigens of multiple sclerosis, part 2: CD8+ T cells, B cells, and antibodies in the focus of reverse-translational research. Lancet Neurol. 15, 317–331 (2016).

    Article  CAS  PubMed  Google Scholar 

  64. Balar, A. V. & Weber, J. S. PD-1 and PD-L1 antibodies in cancer: current status and future directions. Cancer Immunol. Immunother. 66, 551–564 (2017).

    Article  CAS  PubMed  Google Scholar 

  65. Gordon, S. R. et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545, 495–499 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dillard, T., Yedinak, C. G., Alumkal, J. & Fleseriu, M. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary 13, 29–38 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Byun, D. J., Wolchok, J. D., Rosenberg, L. M. & Girotra, M. Cancer immunotherapy — immune checkpoint blockade and associated endocrinopathies. Nat. Rev. Endocrinol. 13, 195–207 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Albarel, F. et al. Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. Eur. J. Endocrinol. 172, 195–204 (2015).

    Article  CAS  PubMed  Google Scholar 

  69. Okano, Y. et al. Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma. Endocr. J. 63, 905–912 (2016).

    Article  PubMed  Google Scholar 

  70. Caturegli, P. et al. Hypophysitis secondary to cytotoxic T-lymphocyte-associated protein 4 blockade: insights into pathogenesis from an autopsy series. Am. J. Pathol. 186, 3225–3235 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Iwama, S. et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci. Transl. Med. 6, 230ra45 (2014).

    Article  PubMed  CAS  Google Scholar 

  72. Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

    Article  PubMed  Google Scholar 

  73. Bot, I., Blank, C. U., Boogerd, W. & Brandsma, D. Neurological immune-related adverse events of ipilimumab. Pract. Neurol. 13, 278–280 (2013).

    Article  PubMed  Google Scholar 

  74. Maur, M. et al. Posterior reversible encephalopathy syndrome during ipilimumab therapy for malignant melanoma. J. Clin. Oncol. 30, e76–e78 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Bien, C. G. et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 135, 1622–1638 (2012).

    Article  PubMed  Google Scholar 

  76. Johnson, D. B. et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2, 234–240 (2016).

    Article  PubMed  Google Scholar 

  77. Menzies, A. M. et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann. Oncol. 28, 368–376 (2017).

    Article  CAS  PubMed  Google Scholar 

  78. Eggermont, A. M. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. Med. 375, 1845–1855 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Dansokho, C. et al. Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain 139, 1237–1251 (2016).

    Article  PubMed  Google Scholar 

  80. Baruch, K. et al. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat. Med. 22, 135–137 (2016).

    Article  CAS  PubMed  Google Scholar 

  81. Goldberg, S. B. et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 17, 976–983 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Weber, J. S. et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J. Clin. Oncol. 35, 785–792 (2017).

    Article  CAS  PubMed  Google Scholar 

  83. Schildberg, F. A., Klein, S. R., Freeman, G. J. & Sharpe, A. H. Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity 44, 955–972 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Boussiotis, V. A. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N. Engl. J. Med. 375, 1767–1778 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Croft, M. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu. Rev. Immunol. 28, 57–78 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Knee, D. A., Hewes, B. & Brogdon, J. L. Rationale for anti-GITR cancer immunotherapy. Eur. J. Cancer 67, 1–10 (2016).

    Article  CAS  PubMed  Google Scholar 

  87. Denoeud, J. & Moser, M. Role of CD27/CD70 pathway of activation in immunity and tolerance. J. Leukoc. Biol. 89, 195–203 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Bartkowiak, T. & Curran, M. A. 4-1BB agonists: multi-potent potentiators of tumor immunity. Front. Oncol. 5, 117 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Sanchez-Paulete, A. R. et al. Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy. Eur. J. Immunol. 46, 513–522 (2016).

    Article  CAS  PubMed  Google Scholar 

  90. Quezada, S. A., Jarvinen, L. Z., Lind, E. F. & Noelle, R. J. CD40/CD154 interactions at the interface of tolerance and immunity. Annu. Rev. Immunol. 22, 307–328 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Yuan, J. et al. Novel technologies and emerging biomarkers for personalized cancer immunotherapy. J. Immunother. Cancer 4, 3 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Dubin, K. et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat. Commun. 7, 10391 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Pitt, J. M. et al. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors. Immunity 44, 1255–1269 (2016).

    Article  CAS  PubMed  Google Scholar 

  94. Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hui, E. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428–1433 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kamphorst, A. O. et al. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355, 1423–1427 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mishra, V., Schuetz, H. & Haorah, J. Differential induction of PD-1/PD-L1 in neuroimmune cells by drug of abuse. Int. J. Physiol. Pathophysiol. Pharmacol. 7, 87–97 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Chen, L. et al. Constitutive neuronal expression of the immune regulator, programmed death 1 (PD-1), identified during experimental autoimmune uveitis. Ocul. Immunol. Inflamm. 17, 47–55 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Ren, X., Akiyoshi, K., Vandenbark, A. A., Hurn, P. D. & Offner, H. Programmed death-1 pathway limits central nervous system inflammation and neurologic deficits in murine experimental stroke. Stroke 42, 2578–2583 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Phares, T. W. et al. Target-dependent B7-H1 regulation contributes to clearance of central nervous system infection and dampens morbidity. J. Immunol. 182, 5430–5438 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Rodig, N. et al. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur. J. Immunol. 33, 3117–3126 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Schreiner, B., Bailey, S. L., Shin, T., Chen, L. & Miller, S. D. PD-1 ligands expressed on myeloid-derived APC in the CNS regulate T-cell responses in EAE. Eur. J. Immunol. 38, 2706–2717 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Pittet, C. L., Newcombe, J., Prat, A. & Arbour, N. Human brain endothelial cells endeavor to immunoregulate CD8 T cells via PD-1 ligand expression in multiple sclerosis. J. Neuroinflammation 8, 155 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. O'Keeffe, G. W., Gutierrez, H., Pandolfi, P. P., Riccardi, C. & Davies, A. M. NGF-promoted axon growth and target innervation requires GITRL–GITR signaling. Nat. Neurosci. 11, 135–142 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hwang, H., Lee, S., Lee, W. H., Lee, H. J. & Suk, K. Stimulation of glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) induces inflammatory activation of microglia in culture. J. Neurosci. Res. 88, 2188–2196 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Anderson, A. C. et al. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 318, 1141–1143 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Wei, D., Ren, C., Chen, X. & Zhao, H. The chronic protective effects of limb remote preconditioning and the underlying mechanisms involved in inflammatory factors in rat stroke. PLoS ONE 7, e30892 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Mao, X. et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353, aah3374 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Abdel-Haq, N., Hao, H. N. & Lyman, W. D. Cytokine regulation of CD40 expression in fetal human astrocyte cultures. J. Neuroimmunol. 101, 7–14 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. Tan, J. et al. CD40 is expressed and functional on neuronal cells. EMBO J. 21, 643–652 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ponomarev, E. D., Shriver, L. P. & Dittel, B. N. CD40 expression by microglial cells is required for their completion of a two-step activation process during central nervous system autoimmune inflammation. J. Immunol. 176, 1402–1410 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Omari, K. M. & Dorovini-Zis, K. CD40 expressed by human brain endothelial cells regulates CD4+ T cell adhesion to endothelium. J. Neuroimmunol. 134, 166–178 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Reali, C. et al. Expression of CD137 and its ligand in human neurons, astrocytes, and microglia: modulation by FGF-2. J. Neurosci. Res. 74, 67–73 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Blank, A. E. et al. Tumour necrosis factor receptor superfamily member 9 (TNFRSF9) is up-regulated in reactive astrocytes in human gliomas. Neuropathol. Appl. Neurobiol. 41, e56–e67 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors' work is supported by INSERM, the French National Centre for Scientific Research (CNRS) and Toulouse III University. R.S.L. is supported by grants from Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques (ARSEP), Midi-Pyrénées Region, Agence Nationale de la Recherche (ANR) T cell-Mig, FP7-PEOPLE-2012-ITN NeuroKine, European Research Area Network (ERA-NET) Meltra-BBB, L'Association pour la Recherche sur le Cancer (ARC) Cancer Research Foundation and Ligue Régionale Contre le Cancer. R.H. is supported by the German Research Foundation (DFG; SFB-TRR128; SyNergy, EXC 1010), German Ministry for Education and Research (BMBF; German Competence Network Multiple Sclerosis), Werner Reichenberger Stiftung, Cyliax Stiftung and Verein Therapieforschung für Multiple Sklerose Kranke. The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. We thank C. Robert, A. Dejean, D. Dunia, G. Martin-Blondel and S. Valitutti for insightful comments on the manuscript.

Author information

Authors and Affiliations

  1. INSERM U1043 — CNRS UMR 5282, Centre de Physiopathologie Toulouse-Purpan, Purpan Hospital, Place du Docteur Baylac TSA 40031, Toulouse, 31059, Cedex 9, France

    Lidia M. Yshii

  2. Institute of Clinical Neuroimmunology, Biomedical Centre and University Hospital, Ludwig Maximilian University, Munich, 80539, Germany

    Reinhard Hohlfeld

  3. Munich Cluster for Systems Neurology (SyNergy), Munich, D-81377, Germany

    Reinhard Hohlfeld

  4. and the Department of Immunology, INSERM U1043 — CNRS UMR 5282, Centre de Physiopathologie Toulouse-Purpan, Purpan Hospital, Place du Docteur Baylac TSA 40031, 31059 Toulouse Cedex 9, France, Hôpital Rangueil, 1, Avenue du Professeur Jean Poulhès — TSA 50032 — 31059 Toulouse Cedex 9, France.,

    Roland S. Liblau

Authors
  1. Lidia M. Yshii
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Reinhard Hohlfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roland S. Liblau
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.M.Y., R.H. and R.S.L. wrote the article. All authors made substantial contributions to discussion of the content and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Roland S. Liblau.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Ongoing or completed immune checkpoint molecule clinical trials (DOC 83 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yshii, L., Hohlfeld, R. & Liblau, R. Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives. Nat Rev Neurol 13, 755–763 (2017). https://doi.org/10.1038/nrneurol.2017.144

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2017.144

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing