Discussion
The majority of HNC was diagnosed at stage III-IV, and its high fatality
rate and poor quality of life become significant concerns to social and
public health (35). HPV, heavy use of tobacco and alcohol can increase
the risk of HNC(36), which has been proved by various studies. Recent
studies have witnessed the development of immunotherapy of HNC. PD-1 was
first discovered and associated with suppressing T cells, downregulating
the immune response, and apoptosis(37). PD-L1(38), one of the ligands of
PD-1, is expressed in T cells and
antigen-presenting cells; PD-L2(39), another ligand of PD-1, is present
in antigen-presenting cells, stromal, tumor endothelial cells, can be
induced by other cells as well(40).
To investigate the effect of PD-1/PD-L1 inhibitors alone or in
combination with traditional therapy, we performed the systematic review
and meta-analysis included five RCTs and nine single-arm clinical
trials, which contained 2,911 HNC patients. The 5 RCTs revealed that
immunotherapy improved survival rates by 63% compared with SOC. The
reasons we inferred are as follows, HNC is characterized by inadequate
immune surveillance, more immunosuppressive cytokines, and impairment of
immune cells both in function and
number(41); immunotherapy may
enhance the capacity of the immunity system to inhibit tumor cell
infiltration. However, DNA repair defects associated with migratory and
invasive behavior may induce the poor prognosis of HNC patients treated
with chemotherapy may induce (42). Of note, conventional therapies are
lack specificity.
We observed patients with HPV+ had better
overall survival (P <0.000001), and participants with PD-L1
CPS ≥1 were more suitable for PD-1/PD-L1 immunotherapy
(P<0.0001). Viral antigens exist as exosomes or integrate into
host cells throughout carcinogenesis (43), which may strengthen the
immunity of HPV+ patients (44). HPV+HNSCC enriched more B cells (44), and PD-1 expression was lower in
CD8+ T
cells, while the PD-1 frequency negatively correlated with IFN-γ
secretion capacity (45). The frequency of PD-1 positive
tumor-infiltrating lymphocytes (TIL) was higher in HPV+patients, but their frequency of
CD4+ regulatory T cells (Tregs) cells was slightly
lower than HPV-TILs(44). The enrichment area of B
cells in HPV+ TIL was found primarily in the germinal
center, in which B cells experienced germinal center reactions and could
appear at different stages of development; while the majority of B cells
in HPV– TILs is mainly plasma cells and switched
memory cells (44). Additionally, TP53 mutations (46), amplification, and
overexpression of CCND1(the gene that encodes Cyclin D1) induced drug
resistance, which was more common on HPV- tumors (47).
PD-L1 overexpression was considered to influence prognosis of HNSCC(48).
PD-L1 on exosomes was associated with disease progression of HNSCC
patients, including patients’ disease activity and the lymph node
status(49). Overexpression PD-L1 on circulating tumor cells (CTC)
indicated worse OS and PFS at the end of treatment for locally advanced
HNSCC(50). In contrast, it was relevant to favorable survival when
overexpression on tumor cells together with tumor-associated immune
cells (TAICs)(47), which seems to be paradoxical and needs more
investigation. Besides, some studies revealed that PD-L2 expression was
the potential prognostic biomarker of PFS and response to pembrolizumab
in HNSCC patients (40), PD-L1 and IFN- γ related gene signatures
impacted effects of PD1/PD-L1 immunotherapy in recurrent or metastatic
HNSCC(47). Intriguingly, patients with high PD-1 expression also have a
better response to PD-1 inhibitors(45).
Although PD-1/PD-L1 immunotherapy influences less on the digestive
system and blood system, it might cause a higher risk of hypothyroidism.
In a report about nivolumab-related thyroiditis, some of the patients
endured transient thyrotoxic phases followed by thyroiditis, part of
them with antithyroglobulin (anti-Tg) and antithyroid peroxidase (TPO)
antibodies. However, thyrotropin binding inhibitory immunoglobulins
(TBII) of all of them were absent, while the other patients developed
hypothyroidism without the thyrotoxic phase, anti-Tg, and anti-TPO
antibodies were positive(51). Some patients with hypothyroidism but
without thyrotoxicosis might endure dormant thyrotoxic stage, and the
mechanism for PD-1/PD-L1 immunotherapy related-thyroid dysfunction was
unclear(52). We assumed PD-1/PD-L1 immunotherapy induced thyroiditis,
thus caused hypothyroidism and the most common fatigue symptoms (52). In
a nutshell, it is necessary to test thyroid function after receiving
PD-1/PD-L1 immunotherapy.