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"Lu, Zhong-Wu"
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Immune Co-inhibitory Receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT in Medullary Thyroid Cancers: A Large Cohort Study
Abstract
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.
Journal Article
Distinct tumor microenvironment makes anaplastic thyroid cancer more lethal but immunotherapy-sensitive than papillary thyroid cancer
Both anaplastic thyroid cancer (ATC) and papillary thyroid cancer (PTC) originate from thyroid follicular epithelial cells, but ATC has a significantly worse prognosis and shows resistance to conventional therapies. However, clinical trials found that immunotherapy works better in ATC than late-stage PTC. Here, we utilized single-cell RNA sequencing (scRNA-seq) to generate a single-cell atlas of thyroid cancer. Differences in ATC and PTC tumor microenvironment (TME) components (including malignant cells, stromal cells, and immune cells) leading to the polarized prognoses were identified. Intriguingly, we found that CXCL13+ T lymphocytes were enriched in ATC samples and might promote the development of early tertiary lymphoid structure (TLS). Lastly, murine experiments and scRNA-seq analysis of a treated patient's tumor demonstrated that Famitinib plus anti-PD-1 antibody could advance TLS in thyroid cancer. Conclusively, we displayed the cellular landscape of ATC and PTC, finding that CXCL13+ T cells and early TLS might make ATC more sensitive to immunotherapy.
Journal Article
A 4 Gene-based Immune Signature Predicts Dedifferentiation and Immune Exhaustion in Thyroid Cancer
Abstract
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.
Journal Article
The impact of marital status at diagnosis on cancer survival in patients with differentiated thyroid cancer
Previous studies have revealed that marital status influences the prognosis of patients with various types of cancer. We evaluated the influence of marriage on the survival outcomes in differentiated thyroid cancer (DTC). The Surveillance, Epidemiology and End Results (SEER) database between 2002 and 2012 was used to compare cancer‐specific mortality in different marital status, and in each sex, age, and stage stratification by multivariate Cox regression model. In total, 61,077 eligible patients were identified. The widowed group had the highest proportion of women, elderly patients (≥45 years), and advanced stage III/IV tumor (P = 0.001), but the total thyroidectomy (TT) performed and radioisotopes therapy rates were lower than those in the married group. Married patients had a better cancer‐specific survival (CSS) than the unmarried (P < 0.05). Further analysis showed that widowed patients always presented the lowest CSS compared with other groups. Widowed patients had a significant increased risk for CSS compared with married patients in males [hazard ratio (HR) 2.72, 95% confidence interval (CI): 1.59–4.65, P = 0.001], females (HR 2.02, 95% CI: 2.24–4.06, P = 0.001), young patients (<45, HR 28.12, 95% CI: 3.48–227.25, P = 0.002), elderly patients (≥45, HR 28.12, 95% CI: 2.97, 95% CI: 2.30–3.83, P = 0.001), stage I (HR 8.44, 95% CI: 4.05–17.59, P = 0.001), stage II (HR 3.64, 95% CI: 1.30–10.20, P = 0.014), stage III (HR 2.27, 95% CI: 1.08–4.78, P = 0.031), and stage IV (HR 2.63, 95% CI: 1.94–3.57, P = 0.001). These results showed that unmarried status, especially for widowhood, increased the risk of cancer mortality in DTC patients. Our results confirmed that the unmarried status has an independent impact on cancer‐specific mortality with a varied risk compared to marriage. Moreover, we indicated that the unmarried patients groups were heterogeneous, and the widowed patients were always at the highest risk of death of cancer than those in other groups.
Journal Article
The Positive Lymph Node Number and Postoperative N-Staging Used to Estimate Survival in Patients with Differentiated Thyroid Cancer: Results from the Surveillance, Epidemiology, and End Results Dataset (1988–2008)
Background
Lymph node metastasis is important when evaluating the prognosis of patients with differentiated thyroid cancer (DTC). However, the current N-staging system cannot fully reflect the clinical significance of cervical lymph node metastasis in DTC. In this study, we employed Surveillance, Epidemiology, and End Results (SEER)-registered DTC cases with lymph node metastasis to determine whether the positive lymph node number (PLNN) could be used to improve stratification of patients in terms of survival.
Methods
We used the SEER dataset to identify all DTC patients with at least one positive cervical lymph node who were examined between 1988 and 2008. Multivariable modeling was used to compare cancer-specific survival (CSS) and overall survival (OS) and to calculate different PLNN cutoff points.
Results
In total, 14,359 pN + DTC patients identified in the SEER were included. In multivariate Cox regression analysis, the PLNN was significantly associated with both CSS and OS, whereas neither the lymph node ratio (LNR) nor the (numbers of) lymph nodes examined (LNE) were so associated. The highest C-index value (0.933) and the lowest AIC value (9362.687) obtained indicated that the PLNN better predicted the CSS of DTC than did the LNR or LNE. As the
p
values for both CSS and OS were minimized, and as the PLNN performed best when cases were grouped, PLNN cutoff points of 10 and 3/10 efficiently stratified DTC patients into two and three levels, respectively. Based on the 3/10 trichotomy, the benefits of radioactive iodine (RAI) treatment were evaluated for each group. Such treatment afforded about a 10% survival benefit in patients with more than 10 lymph node metastases.
Conclusions
Compared with the LNR and LNE under different statistical models, PLNN was superior in terms of DTC staging. A cutoff point of 3/10 was optimal for stratifying patients according to prognosis and was of clinical significance in terms of RAI treatment selection.
Journal Article
IL-17A increases MHC class I expression and promotes T cell activation in papillary thyroid cancer patients with coexistent Hashimoto’s thyroiditis
Background
The incidence of coexisting papillary thyroid cancer (PTC) and Hashimoto’s thyroiditis (HT) is increasing. The impact of HT on PTC prognosis and its possible mechanism remains controversial. Interleukin-17A (IL-17A) has been reported to participate in the pathogenesis of multiple autoimmune diseases and cancers. The aim of this study is to investigate the role of IL-17A in PTC with coexistent HT and evaluate the changes in tumor antigenicity.
Methods
Expression of IL-17A and major histocompatibility complex (MHC) class I molecules were compared on PTC tissue samples with or without HT. PTC cell lines K1 and TPC-1 were stimulated with IL-17A and analyzed for MHC class I expression afterwards. Cluster of differentiation (CD) 8
+
T cell activation, production of Interleukin-2 (IL-2) and Interferon-gamma (IFN-γ) as well as the programmed death-1 (PD-1) expression on lymphocytes were assessed by coculture of donor peripheral blood lymphocytes (PBLs) with IL-17A pretreated PTC cells.
Results
Elevated IL-17A and MHC class I expression were observed in PTC tissue samples with coexistent HT. Stimulation of PTC cells with IL-17A effectively increased MHC class I expression in vitro. Coculture of PBLs with IL-17A pretreated PTC cells resulted in enhanced T cell activation (%CD25
+
of CD3
+
T cells) and increased IL-2 production along with decreased IFN-γ secretion and PD-1 expression of the lymphocytes.
Conclusions
Papillary thyroid cancer with coexisting Hashimoto’s thyroiditis presents elevated MHC class I expression, which may be the result of IL-17A secretion. T cell activation is enhanced in vitro by IL-17A and may provide future utility in PTC immunotherapy.
Journal Article
Silencing of PPM1D inhibits cell proliferation and invasion through the p38 MAPK and p53 signaling pathway in papillary thyroid carcinoma
Endeavors towards identifying key molecular markers for early diagnosis and treatment are driving the clinical study of papillary thyroid carcinoma (PTC). Recent studies have indicated that protein phosphatase, Mg2+/Mn2+ dependent, 1D (PPM1D) exerts an oncogenic function by increasing cell proliferation, migration and invasion in various cancer types. In addition, PPM1D has a high frequency of genetic alterations and has been proposed as a tumor driver in thyroid cancer, making PPM1D an attractive potential oncotarget for cancer treatment. The aims of the present study were to investigate the downstream targets of PPM1D and the potential molecular mechanisms of its oncogenic activities, as well as its clinical significance in PTC. As anticipated, PPM1D overexpression was confirmed in PTC clinical specimens. Furthermore, knockdown of PPM1D in thyroid cancer cell lines significantly suppressed the proliferation, migration and invasion but facilitated cell apoptosis. The protein levels of phosphorylated p38 mitogen-activated protein kinase (MAPK), p53 and Bax were increased in PPM1D-knockdown cells, while inhibition of p38 phosphorylation restored cell migration, proliferation and cell apoptosis. In addition, silencing of PPM1D expression induced nuclear translocation of p53 in K-1 and TPC-1 cells. The present results demonstrated that PPM1D regulated p38 MAPK and p53 signaling pathways to promote thyroid cancer progression. Collectively with the clinical results, these data qualified PPM1D as a potential diagnostic biomarker and therapeutic target in human thyroid cancer.
Journal Article
Risk prediction and clinical model building for lymph node metastasis in papillary thyroid microcarcinoma
The surgical management of papillary thyroid microcarcinoma (PTMC), especially regarding the necessity of central/lateral lymph node dissection, remains controversial. This study investigated the clinicopathologic factors predictive of lymph node metastasis (LNM) in patients diagnosed with PTMC. Multivariate logistic regression analysis was used for PTMC patients identified from the Surveillance, Epidemiology, and End Results database who were treated by surgery between 2002 and 2012, to determine the association of clinicopathologic factors with LNM. According to the results, a total of 31,017 patients met the inclusion criteria of the study. Final histology confirmed 2,135 (6.9%) cases of N1a disease and 1,684 cases (5.4%) of N1b disease. Our multivariate logistic regression analysis identified variables associated with both central LNM and lateral lymph node metastasis (LLNM), including a younger age (<45 years), male sex, non-Hispanic white and other race, classical papillary histology, larger tumor size, multifocality, and extrathyroidal extension; distant metastasis was also significantly associated with LLNM. The significant predictors identified from multivariable logistic regression were integrated into a statistical model that showed that extrathyroidal extension had maximum weight in the predictive role for LNM. LLNM was validated to be a significant risk factor for cancer-specific death in Cox regression analyses, whereas central LNM failed to predict a worse cancer-specific survival according to our data. Therefore, we suggested that central lymph node dissection could be performed in certain patients with risk factors. Given the prevalence of LLNM in PTMC, a thorough inspection of the lateral compartment is recommended in PTMC patients with risk factors for precise staging; from the viewpoint of a radical treatment for tumors, prophylactic lateral lymph node dissection that aims to remove the occult lateral lymph nodes may be an option for PTMC with risk factors. Multicenter studies with long-term follow-up are recommended to better understand the risk factors and surgical management for cervical nodes in PTMC.
Journal Article
Downregulation of CSN6 attenuates papillary thyroid carcinoma progression by reducing Wnt/β‐catenin signaling and sensitizes cancer cells to FH535 therapy
The incidence of thyroid cancer has increased worldwide at a rate higher than that of any other cancer. CSN6 is overexpressed in many types of cancers, and such expression is linked to oncogenic activity. However, the detailed biological functions of CSN6 in papillary thyroid cancer (PTC) have not been well characterized. We investigated CSN6 expression in PTC specimens and cell lines. We used short‐hairpin RNA‐mediated gene silencing to explore the biological effects of CSN6 depletion in PTC cells. The combined effects of CSN6 silencing and FH535 therapy were assessed in terms of cell viability. The mechanism by which CSN6 regulated β‐catenin expression was also analyzed. CSN6 levels were determined by real‐time polymerase chain reaction (PCR) (mRNA), Western blotting, and immunochemistry (protein). The CCK‐8 and migration assays and orthotopic xenograft transplantation were used to investigate the biological effects of CSN6. We assessed the combined effects of CSN6 silencing and FH535 on cell viability in vitro. We also analyzed the relationship between the CSN6 level and clinical pathological status. CSN6 was overexpressed in human PTCs, and loss of CSN6 attenuated tumor proliferation and migration both in vitro and in vivo. CSN6 stabilized β‐catenin and facilitated the epidermal‐to‐mesenchymal transition (EMT) in PTC cells. CSN6 positively regulated β‐catenin expression in a β‐Trcp‐dependent manner and triggered expression of several EMT‐related genes regulated by β‐catenin. CSN6 silencing sensitized PTC cells to FH535 therapy via downregulation of the Wnt/β–catenin signaling pathway. Finally, in PTC patients, the level of CSN6 was significantly (inversely) correlated with tumor size, the presence of multifocal lesions, and TNM stage. CSN6 overexpression in PTC is a strong indicator of enhanced tumor aggressiveness. CSN6 promotes PTC progression by inducing the EMT. CSN6 knockdown sensitizes PTC cells to FH535 therapy via downregulation of the Wnt/β–catenin signaling pathway. CSN6 was overexpressed in human PTCs, and loss of CSN6 attenuated tumor proliferation and migration. In PTC patients, the level of CSN6 was significantly (inversely) correlated with tumor size, the presence of multifocal lesions, and TNM stage.
Journal Article