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Cencioni. Neuroimmunol Neuroinflammation 2020;7:277-90 I http://dx.doi.org/10.20517/2347-8659.2020.18 Page 285

including CTL-4, PD-1 and TIM-3, decreased in patients with MS as compared with healthy controls [104] .
PD-1 is usually the most downregulated gene among the investigated inhibitors [104] . PD-1 was analysed on
+
+
cytotoxic CD8 CD57 T cells in the peripheral blood of patients with relapsing–remitting MS and in T cells
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infiltrating the brain tissue in post-mortem MS cases. PD-1 increased in CD8 CD57 T cells in patients
+
with stable disease and decreased in active-relapsing MS compared with healthy donors [105] . PD-1 was also
found to increase in CD4 and CD8 T cells in MS patients early after autologous hematopoietic stem cell
transplant [106] . A study of long-term immune reconstitution in MS patients after autologous hematopoietic
+
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stem cell transplant demonstrated that an early expansion of CD8 PD-1 T cells and CD19 PD-1 B cells
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is associated with favourable neurological outcomes [106] . PDL-1 was also investigated in post-mortem MS
brain tissue. In MS lesions, glial cells with elevated PDL-1 and PD-1 expression were found absent in many
[94]
infiltrating CD8 T cells . Moreover, PDL-2 but not PDL-1 is expressed in human brain endothelial cells
under basal culture conditions whilst both are upregulated under inflammatory condition [107] . PDL-1 or
[94]
PDL-2 blockade lessens CD8 and CD4 T cell transmigration and CD8 T cells response . Furthermore,
PDL-1 is undetectable in the brain endothelium in normal tissues and MS lesions, even though PDL-2 is
[94]
detectable in all blood vessels in normal brain tissue and in 50% of MS lesions .
MULTIPLE SCLEROSIS DIAGNOSIS AFTER CANCER IMMUNOTHERAPY
ICI treatments are immunotherapies engaged in restoring the immune response to tumour or viral
infection by blocking the inhibitory pathways mediated by CTLA-4 and PD-1. ICI treatments have induced
neurological immune-related adverse events. Patients with an MS history developed relapses after ICI
treatment for melanoma [108,109] and a biopsy of the lesions revealed acute/inflammatory demyelination
without any evidence of tumour cells [109] . A comparative functional profiling of myelin-reactive T cells
of patients after ICI- treatment and 14 age/sex-matched patients with MS and healthy controls was
performed. Myelin-reactive T cells isolated from ipilimumab-treated patients and MS patients showed a
similar autoimmune response to myelin antigen but distinct from healthy controls. That confirmed that
ICI treatment causes a reactivation of self-antigen cells in MS patients. The lack of outcomes to the ICI
treatment in tumour is associated with an effect on the neurological condition. A case reported maintaining
stable MS during ipilimumab treatment for melanoma that did not respond to the therapy, and the patient
died from metastatic melanoma [110] .

Furthermore, a 29-year-old man with metastatic melanoma underwent two cycles of ipilimumab before
developing MS. The TCR repertoires of tumour-infiltrating T cells isolated from the primary melanoma
and those of T cells isolated in two CSF samples, five and thirteen months after the second course of
ipilimumab therapy, were analysed and compared. Distinct clonotypes of CD4 and CD8 T cells in the
melanoma and the CSF were identified, demonstrating that the protective antitumor response and the anti-
CNS response target different antigens [111] . Outcomes of MS relapse after ICI treatment were reported in
a meta-analysis study including the published literature, the analysis of food and the drug administration
adverse event reporting system database and a detailed case [112] . Fourteen cases were identified with MS,
of which eight had a reported history of MS. All patients presented rapid disease progression, and two
of them died from severe MS after ICI treatment [112] . The median age of MS diagnosis was 52.5 years,
and ICI treatment was used as immunotherapy in several types of cancer: melanoma, non-small cell
lung carcinoma, pleural mesothelioma, renal cell carcinoma and colorectal cancer [112] . ICI treatments
such as nivolumab, ipilimumab, pembrolizumab and atezolizumab have caused MS relapse. In addition,
Isitan and Wesley [113] described the case of a 49-year-old woman with a history of relapsing–remitting
MS reported to develop a severe progressive MS after atezolizumab (monoclonal antibody targeting PD-
L1) therapy for metastatic colonic adenocarcinoma. The women died after her first dose of atezolizumab.
Although ICI therapy has given beneficial outcomes in cancer and infectious diseases, this treatment has
shown neurological side effects in patients with MS history, inducing a rapid worsening of neurological
conditions. The examined cases showed a worsening of the conditions associated with the activation of T