A 4 Gene-based Immune Signature Predicts Dedifferentiation and Immune Exhaustion in Thyroid Cancer.

CONTEXT: The role of immune-related genes (IRGs) in thyroid cancer dedifferentiation and accompanying immune exhaustion remains largely unexplored. OBJECTIVE: To construct a significant IRG-based signature indicative of dedifferentiation and immune exhaustion in thyroid cancer. DESIGN AND SETTINGS: One exploratory cohort and 2 validation cohorts were used to identify stably dysregulated IRGs in dedifferentiated thyroid cancer (DDTC) and to obtain independent risk factors for dedifferentiation. The IRGs formed a gene signature, whose predictive value was tested by the receiver operating characteristic curve. Correlations between the signature and differentiation-related genes, immune checkpoints, and prognosis were analyzed. Gene set enrichment analyses were performed to identify related signaling pathways. RESULTS: Four IRGs (PRKCQ, PLAUR, PSMD2, and BMP7) were found to be repeatedly dysregulated in DDTC, and they formed an IRG-based signature with a satisfactory predictive value for thyroid cancer dedifferentiation. Correlation analyses revealed that immune checkpoints were closely related to the 4 IRGs and the IRG-based signature, which was significantly associated with the histological subtype (P = 0.026), lymph node metastasis (P = 0.001), and BRAFV600E mutation (P < 0.001). The downregulated expression of PRKCQ shortened the disease-free survival for patients with thyroid cancer. Furthermore, we identified several signaling pathways inherently associated with the IRG-based signature. CONCLUSIONS: This study suggests that IRGs participate in the dedifferentiation and immune exhaustion process of thyroid cancer and are potential biomarkers for DDTC.

Immune Co-inhibitory Receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT in Medullary Thyroid Cancers: A Large Cohort Study.

CONTEXT: Programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin and ITIM domain (TIGIT) are considered major immune co-inhibitory receptors (CIRs) and the most promising immunotherapeutic targets in cancer treatment, but they are largely unexplored in medullary thyroid carcinoma (MTC). OBJECTIVE: We aimed to provide the first evidence regarding the expression profiles and clinical significance of CIRs in a large cohort of MTC patients. DESIGN AND PATIENTS: In total, 200 MTC patients who received initial surgery in our hospital were included. Immunohistochemistry was performed to evaluate CIR expressions in tissue microarrays (TMAs). Combined with the results of our previous programmed cell death ligand-1 (PD-L1) study, clinicopathologic and prognostic correlations of these proteins were retrospectively analyzed. RESULTS: TIM-3, PD-1, CTLA-4, LAG-3, and TIGIT positivity was detected in 96 (48.0%), 27 (13.5%), 25 (12.5%), 6 (3.0%), and 6 (3.0%) patients, respectively, in whom TIM-3, PD-1, and CTLA-4 expressions were positively correlated. Log-rank tests and multivariate Cox analyses both indicated that TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression were associated with worse structural recurrence-free survival. In addition, among 20 patients who developed advanced disease during follow-up, 12 (60%) showed TIM-3 positivity, among whom 6 cases also had concurrent moderate to strong PD-1, PD-L1, or CTLA-4 expression. CONCLUSIONS: Using the currently largest TMA cohort of this rare cancer, we delineated the CIR expression profiles in MTC, and identified TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression as promising biomarkers for tumor recurrence. Furthermore, a subset of advanced MTCs are probably immunogenic, for which single or combined immunotherapy including TIM-3, PD-1, PD-L1, or CTLA-4 blockade may be potential therapeutic approaches in the future.

Treating Clinically Node-Negative Insular Thyroid Carcinoma without Prophylactic Central Compartment Neck Dissection Is Associated with Decreased Survival Regardless of T Staging and Administration of Radioactive Iodine Therapy: The First Evidence.

For the rare but aggressive insular thyroid carcinoma (ITC), there's no clear evidence to determine whether prophylactic central compartment neck dissection (CCND) is necessary for cN0 disease. This study provides the first evidence that treating cN0 ITC without prophylactic CCND is associated with decreased survival regardless of T staging and administration of RAI therapy. Background. Regarding the rare but aggressive insular thyroid carcinoma (ITC), the value of prophylactic central compartment neck dissection (CCND) for clinically node-negative (cN0) disease is unclear. We aimed to provide the first evidence. Methods. N0 and pN1a ITC patients were identified from the Surveillance, Epidemiology, and End Results database. These patients were divided into thyroid-surgery + CCND group (pN0/pN1a patients confirmed by CCND) and thyroid-surgery group (cN0 patients without CCND). Differences in overall survival (OS) and disease-specific survival (DSS) between the two groups were evaluated. Subgroup analyses were also conducted. Results. Of the overall 112 patients, 44 (39.3%) received CCND. On multivariate analyses, the lobectomy ± isthmusectomy/total-thyroidectomy (Lob/TT) group demonstrated poorer OS and DSS than the Lob/TT + CCND group (P < 0.05). When we separately analyzed patients treated by TT, multivariate analyses showed the TT group still revealed compromised OS and DSS than the TT + CCND group (P < 0.05). Furthermore, absence of CCND independently predicted decreased OS no matter whether radioactive iodine (RAI) was administered. Similar results were obtained for T3/T4 patients. Moreover, for T1/T2 patients receiving CCND, 0/12 died during the study period, while for T1/T2 patients without CCND, 8/23 (34.8%) died, 5/23 (21.7%) due to ITC. Conclusion. Regardless of T staging and RAI treatment, cN0-ITC patients without CCND had decreased survival compared with pN0/pN1a patients receiving CCND. Therefore, if a cN0 patient is diagnosed with ITC, prophylactic CCND may be considered as a secondary procedure (postoperatively diagnosed) or a primary procedure (preoperatively/intraoperatively diagnosed). Prospective studies are expected to validate the conclusion.

Association Between Programmed Death-Ligand 1 Expression and Clinicopathological Characteristics, Structural Recurrence, and Biochemical Recurrence/Persistent Disease in Medullary Thyroid Carcinoma.

Background: Expression of the programmed death-ligand 1 (PD-L1) in medullary thyroid carcinoma (MTC) has been rarely reported. In this study, we evaluated PD-L1 positivity in MTC and analyzed its correlation with clinicopathological characteristics, structural recurrence (SR), and biochemical recurrence/persistent disease (BcR/BcPD). We also evaluated the prevalence of PD-L1 expression in patients developing distant or unresectable locoregional recurrence. Methods: In total, 201 consecutive MTC patients who underwent initial surgery in our institution from January 2006 to December 2015 were included. PD-L1 expression was evaluated by immunohistochemical staining and was considered positive in case of a combined positive score ≥1. The association of PD-L1 positivity with clinicopathological characteristics, structural recurrence-free survival (SRFS), and BcR/BcPD was retrospectively investigated. Results: The median follow-up length of the entire cohort was 73 months. We observed positive PD-L1 staining in 29 (14.4%) patients who were more likely to have a larger tumor size (p = 0.002), lymph node metastases (p = 0.036), and advanced TNM staging (p = 0.019). The five-year SRFS of the PD-L1-negative and PD-L1-positive groups was 85.4% and 57.9% (p = 0.001). Multivariate Cox analysis showed that PD-L1 positivity was independently associated with SR (hazard ratio = 2.19 [95% confidence interval (CI) 1.01-4.77], p = 0.047). Furthermore, multivariate logistic analysis showed that PD-L1 positivity was significantly associated with BcR/BcPD (odds ratio = 3.16 [CI 1.16-8.66], p = 0.025). During the study period, 20 patients developed distant or unresectable locoregional recurrence, among whom 8 (40%) were PD-L1 positive, which was much higher than in the entire MTC population. Conclusions: Using a large cohort of MTC patients, we demonstrate that PD-L1 positivity is associated with aggressive clinicopathological features and is independently predictive of SR and BcR/BcPD. Furthermore, a higher rate of PD-L1 expression in patients with incurable recurrence has been observed. Therefore, immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/PD-L1 pathway may be a potential therapeutic strategy to treat advanced MTC.