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Cencioni. Neuroimmunol Neuroinflammation 2020;7:277-90 I http://dx.doi.org/10.20517/2347-8659.2020.18 Page 279
[17]
immunodeficiency virus (HIV) and hepatitis B and C virus (HBV, HCV) [18,19] . The loss of antiviral
activity on CD8 T cells is associated with the upregulation of PD-1 in an animal model of LCMV followed
[20]
by hierarchy suppression of cyto- and cytotoxic function . The CD8 cytotoxic function against infected
cells and antiviral cytokines production can be restored by blocking the PD-1/PDL-1 pathway, leading to
clearance of infection in LCMV. The PD-1/PDL-1 pathway is the principal regulator of T-cell exhaustion
in the animal model of LCMV. Studies on PD-1 in human chronic infections such as Human HIV and
HCV have shown an increase of PD-1 on virus-specific CD8 T cells. PD-1 increases in HIV-specific
CD4 and CD8 T cells and is directly correlated with the viral load and inversely with CD4 T cell counts.
Furthermore, PD-1 increases in patients with HIV progression as compared with patients with long-term
progression.

Moreover, T-cell exhaustion suppresses cancer immune-surveillance, leading to tumour spread. Restoring
the immune surveillance by blocking PD-1/PDL-1 pathway has been an essential improvement in the
cancer treatment. The function of PD-1 and its deregulations are summarised in Figure 1.

Nonetheless, some tumours develop resistance to PD-1 blocking, which is regulated by the tumour
microenvironment where infiltrates of regulatory and immune suppressor cells (myeloid suppressor cells,
regulatory T cells, immature dendritic cells and immune-suppressive macrophages) reduce the activity of
cytotoxic CD8 T cells. Any treatment that induces changes in the levels of hormones and growth factors
increases the vulnerability of cancer cells to cytotoxic drugs, which become sensitive to PD-1 treatment.
Furthermore, short-term starvation (STS) has been described to reduce levels of insulin-like growth factor
1 (IGF-1) in the lung cancer microenvironment with an increase in the infiltration of immune cells and
[21]
cytotoxic CD8 T cells . The combining of PD-1 blockade treatment with STS boosts the immune system,
reducing the tumour size significantly in a mouse model of KRAS-driven lung adenocarcinoma and
[21]
Lewis lung carcinoma . The combination of the two treatments induced in the mice an extended lasting
memory response. The immunological study has shown an increase in tumour-infiltrating CD8 and natural
killer cells by reducing the proportion of CD4 and B cells. CD8 and CD4 T cells showed a reduction in
PD-1 expression. Depletion of CD8 T cells abrogated utterly the effect of the STS and anti-PD-1 treatment,
confirming that STS sensitises the lung cancer to CD8 T cells reactivated by PD-1 blocking. The tumour-
immune infiltrate treated with anti-PD-1 after STS was analysed with a flow cytometer and presented an
increase in the frequency of tumour-specific IFN-g-producing T cells as compared with mice treated with
only one agent or vehicle .
[21]
A selective ablation of PD-1 on myeloid cells or T cells has essentially contributed to understanding the
function of PD-1 in the cancer-immunity cycle. Mice with PD-1 ablated only on myeloid cells showed an
increase of effector memory T cells and an enhanced response against the tumours. Ablation of PD-1 on
myeloid cells changes the tumour microenvironment, skewing the myeloid cell fate toward differentiation
+
+
of monocytes, macrophages and CD11c MHCII dendritic cells (DC) rather than myeloid suppressor
cells and granulocyte/macrophage progenitors. The reduction of myeloid suppressor cells due to PD-1
ablation contributes to restoring the functionality of effector memory T cells and, consequently, an immune
[22]
response to the tumour .

PD-1/PDL-1 AXIS IN AUTOIMMUNE DISEASE
Autoimmune thyroid diseases (AIDTs) are an organ-specific autoimmune disease that affects 50/100,000
people per year, with a prevalence in females . Infiltrating lymphocytes generating follicle structures are
[23]
described in the thyroid glands in Hashimoto thyroiditis and Grave’s disease (GD), the most common
AIDTs . Interferon signalling and increased expression of PD-1 and M2 macrophages markers were
[24]
[25]
revealed in the transcriptomic analysis of GD glands . Thyroid autoimmunity is one of the most common
[26]
Immune-Related Adverse Events observed after immune checkpoint inhibitors (ICI) treatments in cancer .