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Page 12 of 19 Matrone et al. J Cancer Metastasis Treat 2021;7:23 https://dx.doi.org/10.20517/2394-4722.2021.47

Several molecules are able to regulate the immune response, mainly through its inhibition. Immunotherapy
aims to enhance the immune response against cancer cells, and, particularly, ICIs block the inhibitory
activity of immune checkpoints. ICIs are monoclonal antibodies which target several immune checkpoints
such as the cytotoxic T-lymphocyte antigen (CTLA-4), the programmed cell death 1 receptor (PD-1), and
its ligand (PD-L1) [Figures 1 and 2]. To our knowledge, there have been no studies or clinical trial designed
against thyroid cancer for ICIs targeting CTLA-4. For this reason, we focus our attention on the PD-1/PD-
L1 pathway.

PD-1/PD-L1 pathway
Most studies evaluating the expression of the PD-1/PD-L1 pathway in thyroid cancer have been focused on
follicular cell-derived tumors, including DTC, PDTC, and ATC. The PD1/PD-L1 pathway is highly
expressed in DTC compared to benign tissues . It is more diffuse in ATC patients , and its level is
[114]
[113]
higher in BRAFV600E PTC compared to BRAF wild-type tumors . The prognostic role of PD-L1 is still
[115]
controversial since it is associated with higher risk of recurrence and a shorter disease-free survival .
[116]
Conversely, in a large cohort of follicular-derived thyroid cancer patients, it is not associated with disease
progression . According to these findings, clinical trials were performed to evaluate the efficacy of
[117]
immunotherapy. The antitumor activity of pembrolizumab (anti-PD-1 antibody) in patients with advanced
[118]
PTC and FTC was limited (9.1% of patients showed a partial response) . Other trials are ongoing, but the
results are still not available (ClinicalTrials.gov, numbers NCT03012620 and NCT02973997).

Concerning MTC, the potential role of immunotherapy could be associated to the immune reactivity of
tumor cell lysates, which usually allowed the exposure of a wide variety of antigens [119,120] , and the subsequent
use of dendritic cell-based vaccinations using CT or CEA antigen [121-123] .

The knowledge about the expression of immune checkpoint in MTC is increasing in the last years. The
expression of PD-1/PD-L1 in MTC seems to be lower than in DTC. Bongiovanni et al. showed low
[124]
expression of PD-L1 in 16 MTC: only in one case was the PD-L1 percentage of expression higher than 1% in
malignant cells, considered as positive cut-off, and two cases showed positivity for PD-L1 in immune cells.

Conversely, Bi et al. showed higher level of expression of PD-1/PD-L1 in MTC patients: PD-1 was
[125]
present on 25.3% (22/87) of the tumor-infiltrating immune cells, and 21.8% (19/87) had positive PD-L1
staining on tumor and immune cells. Moreover, in this study, the expression of PD-L1 in tumor cells and
immune cells correlated with distant metastases at the time of surgery. Pozdeyevet al. showed PD-L1
[126]
expression in 46 MTC patients: it was detected in 32% and 26% of primary tumors and metastases,
[127]
respectively. Shi et al. reported a lower positivity of the PD-L1 expression (14%) in 201 MTC patients at
immunohistochemical staining. PD‐L1 positivity was associated with larger tumor size, lymph node
metastases, higher TNM staging, structural recurrence, biochemical recurrence/persistent disease and a
lower 5-year structural recurrence‐free survival rate (57.9% vs. 85.4%). In a subsequent study , the same
[128]
authors explored the expression of multiple immune checkpoints in MTC. They found that TIM-3 (T-cell
immunoglobulin and mucin-domain containing-3) was the most expressed (48%), and, in most of the cases,
it was expressed exclusively on tumor cells and correlated with older age at diagnosis and advanced staging.
PD-1 positivity was observed in 13.5% of cases, and about half (44.4%) of them had concurrent PD-L1
expression; CTLA-4 was present in 12.5%, while LAG-3 (lymphocyte activation gene-3) and TIGIT (T cell
immunoglobulin and ITIM domain) were positive in 3% of patients. Moreover, the expression of these
molecules correlated with clinical outcome: the rate of structural recurrence was significantly higher in
positive patients for TIM-3, CTLA-4, and PD-1/PD-L1, and 80% of 20 patients who developed advanced
disease during the follow-up period had single or multiple immune checkpoint expressions.