Circulating Myeloid-Derived Suppressor Cells Predict Differentiated Thyroid Cancer Diagnosis and Extent

Abstract

Background: Establishing the preoperative diagnosis and long-term prognosis of differentiated thyroid cancer (DTC) remain challenging in some patients. Myeloid-derived suppressor cells (MDSC) are tumor-induced cells mediating immune tolerance that are detectable in the peripheral blood of cancer patients. The authors previously developed a novel clinical assay to detect the phenotypes of two human MDSC subsets in peripheral blood, and hypothesize that higher MDSC levels measured by this assay correlate positively with both ma-lignancy and worse patient outcomes. Methods: A prospective observational pilot study was performed of patients undergoing thyroidectomy for a solitary thyroid nodule. The presence of a thyroid nodule >1 cm was confirmed sonographically, and fine-needle aspiration biopsy performed prior to surgery in all cases. Peripheral blood collected preoperatively was analyzed using a novel flow cytometry-based immunoassay to detect and quantify two subsets of human MDSC. Circulating MDSC levels were compared by histopathologic diagnosis, stage, and presence of persistent disease after treatment. Results: Of 50 patients included in this study, MDSC measurement was successful in 47 (94%). One patient was found to have a concurrent cancer, leaving 46 patients for primary analysis. The cytologic diagnoses were benign in five (10.8%), atypia or follicular lesion of undetermined significance in five (10.8%), suspicious for follicular neoplasm in five (10.8%), suspicious for malignant in three (6.5%), and malignant in 28 (60.1%) of the 46 nodules. Final histopathology was benign in 11 (24%) and DTC in 35 (76%), encompassing 34 PTC cases and one follicular thyroid carcinoma. Mean percentages of CD11b + HLA-DR low HIF1a + MDSC (CD11b + MDSC) were 14.0-6.2% and 7.9-3.6% in DTC versus benign nodules, respectively (p < 0.005). A cutoff of 12% yielded a specificity of 0.91, a sensitivity of 0.72, and a likelihood ratio of 7.9. Mean CD11b + MDSC levels increased linearly with higher TNM stage (p < 0.01), and were 19.4-5.4 in patients with persistent cancer after surgery compared with 13.2-6.8 in those without evidence of disease (p < 0.05). Conclusion: MDSC measurement using this flow cytometry-based assay represents a novel approach for pre-operatively assessing malignancy risk and cancer extent in patients with thyroid nodules. While further validation is needed, these data suggest that MDSC assessment may serve as a useful adjunct when cytology is indeterminate , and predict tumor stage and recurrence risk in cases of thyroid cancer.

Anti‐PD‐1/PD‐L1 therapy augments lenvatinib's efficacy by favorably altering the immune microenvironment of murine anaplastic thyroid cancer

“…demonstrated that blood PMN‐MDSC correlate with the stage and persistence of DTC, and Suzuki et al . demonstrated increased levels of circulating MDSCs in patients with ATC …”

Detecting Prostate Cancer Using Pattern Recognition Neural Networks With Flow Cytometry-Based Immunophenotyping in At-Risk Men

“…Several studies have indicated that as the tumor progresses there is an increase of MDSCs found in circulation. [21][22][23][24] On grouping patients with PCa by Gleason scores, we generally did not observe this with the only exception being between Gleason score 6 (G6) and Gleason score 7 (G7) for PMN-MDSCs ( Figure 2). More interestingly, there was a trend for M-MDSC levels to decrease with tumor progression, and unexpectedly, patients with BPH had a higher median level of M-MDSCs than patients with PCa albeit not statistically significant.…”

“…Given that MDSC populations have been shown to be present in higher numbers in patients with cancer, we wanted to determine whether their gated counts could be used as an effective tool for detecting PCa. [21][22][23][24] The AUCs using the gated population percentage of live cells for eMDSCs, PMN-MDSCs, and M-MDSCs between HDM and patients with PCa were found to be 0.6791 (95% confidence interval [CI]: 0.6109-0.7472), 0.5178 (95% CI: 0.4457-0.5900), and 0.5473 (95% CI: 0.4745-0.6201), respectively ( Figure 1Q). The AUCs for all other measured populations based on gated percentage of live cells were determined, and CD14 + monocytes, CD16 − PMN, CD3 + lymphocytes, CD3 + T cells, CD4 + T cells, NKT cells, CD4 + NKT cells, CD8 + NKT cells, NK cells, and B cells were found to have AUCs greater than 0.6-all values greater than what was found for the PMN-MDSC and M-MDSC populations ( Supplementary Table S3).…”

Immune responses in the thyroid cancer microenvironment: making immunotherapy a possible mission

“…In thyroid cancers, the presence of MDSCs may even be a useful biomarker for distinguishing benign nodules from cancerous lesions. Specifically, there seems to be an association between higher preoperative levels of circulating MDSCs and thyroid cancers as compared to patients with benign nodules or other non-cancerous thyroid diseases (Suzuki et al 2013, Angell et al 2016. There also seems to be a correlation between numbers of circulating MDSCs and aggressive growth characteristics of differentiated thyroid cancers (Angell et al 2016).…”

“…Specifically, there seems to be an association between higher preoperative levels of circulating MDSCs and thyroid cancers as compared to patients with benign nodules or other non-cancerous thyroid diseases (Suzuki et al 2013, Angell et al 2016. There also seems to be a correlation between numbers of circulating MDSCs and aggressive growth characteristics of differentiated thyroid cancers (Angell et al 2016). Prognoses could potentially be improved in thyroid cancer patients by either differentiating MDSCs into mature myeloid cells or depleting or functionally inhibiting them with various treatments, including some chemotherapeutics, nitric oxide inhibitors, tyrosine kinase inhibitors (e.g.…”