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Reprogramming of myeloid cells and their progenitors in patients with non-medullary thyroid carcinoma.

ABSTRACT: Myeloid cells, crucial players in antitumoral defense, are affected by tumor-derived factors and treatment. The role of myeloid cells and their progenitors prior to tumor infiltration is poorly understood. Here we show single-cell transcriptomics and functional analyses of the myeloid cell lineage in patients with non-medullary thyroid carcinoma (TC) and multinodular goiter, before and after treatment with radioactive iodine compared to healthy controls. Integrative data analysis indicates that monocytes of TC patients have transcriptional upregulation of antigen presentation, reduced cytokine production capacity, and overproduction of reactive oxygen species. Interestingly, these cancer-related pathological changes are partially removed upon treatment. In bone marrow, TC patients tend to shift from myelopoiesis towards lymphopoiesis, reflected in transcriptional differences. Taken together, distinct transcriptional and functional changes in myeloid cells arise before their infiltration of the tumor and are already initiated in bone marrow, which suggests an active role in forming the tumor immune microenvironment.

SUBMITTER: Rabold K

PROVIDER: S-EPMC9579179 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Reprogramming of myeloid cells and their progenitors in patients with non-medullary thyroid carcinoma.

Rabold Katrin K Zoodsma Martijn M Grondman Inge I Kuijpers Yunus Y Bremmers Manita M Jaeger Martin M Zhang Bowen B Hobo Willemijn W Bonenkamp Han J HJ de Wilt Johannes H W JHW Janssen Marcel J R MJR Cornelissen Lenneke A M LAM van Engen-van Grunsven Ilse C H ICH Mulder Willem J M WJM Smit Jan W A JWA Adema Gosse J GJ Netea Mihai G MG Li Yang Y Xu Cheng-Jian CJ Netea-Maier Romana T RT

Nature communications 20221018 1

Myeloid cells, crucial players in antitumoral defense, are affected by tumor-derived factors and treatment. The role of myeloid cells and their progenitors prior to tumor infiltration is poorly understood. Here we show single-cell transcriptomics and functional analyses of the myeloid cell lineage in patients with non-medullary thyroid carcinoma (TC) and multinodular goiter, before and after treatment with radioactive iodine compared to healthy controls. Integrative data analysis indicates that ...[more]

PMID: 36257966

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Project description:Lenvatinib is a multitarget tyrosine kinase inhibitor (TKI) approved for the treatment of several types of cancers, including metastatic differentiated thyroid cancer (DTC). The intended targets include VEGFR 1-3, FGFR 1-4, PDGFRα, RET, and KIT signaling pathways, but drug resistance inevitably develops and a complete cure is very rare. Recent data has revealed that most of the TKIs have additional 'off-target' immunological effects, which might contribute to a protective antitumor immune response; however, human cellular data are lacking regarding Lenvatinib-mediated immunomodulation in DTC. Here, we investigated in ex vivo models the impact of Lenvatinib on the function of immune cells in healthy volunteers. We found that monocytes and macrophages were particularly susceptible to Lenvatinib, while neutrophiles and lymphocytes were less affected. In tumor-immune cell co-culture experiments, Lenvatinib exerted a broad inhibitory effect on the proinflammatory response in TC-induced macrophages. Interestingly, Lenvatinib-treated cells had decreased cellular M2 membrane markers, whereas they secreted a significantly higher level of the anti-inflammatory cytokine IL-10 upon LPS stimulation. In addition, prolonged exposure to Lenvatinib impaired macrophages survival and phenotypical differentiation, which was accompanied by remarkable morphological changes and suppressed cellular metabolic activity. These effects were mediated by myeloid cell-intrinsic mechanisms which are independent of Lenvatinib's on-target activity. Finally, using specific inhibitors, we argue that dual effects on p38 MAPK and Syk pathways are likely the underlying mechanism of the off-target immunological effects we observed in this study. Collectively, our data show the immunomodulatory properties of Lenvatinib on human monocytes. These insights could be harnessed for the future design of novel treatment strategies involving a combination of Lenvatinib with other immunotherapeutic agents.

Project description:BackgroundTherapeutic options for treating advanced or metastatic medullary thyroid carcinoma (MTC) and anaplastic thyroid carcinoma (ATC) are still limited in Japan, even though vandetanib for MTC and lenvatinib for MTC and ATC have been approved. Sorafenib is an oral multikinase inhibitor approved for the treatment of patients with radioactive iodine-refractory differentiated thyroid cancer (DTC). An uncontrolled, open-label, multicenter, single-arm, Phase 2 clinical study was conducted to evaluate the safety and efficacy of sorafenib in Japanese patients with MTC and ATC.MethodsJapanese patients with histologically confirmed ATC and locally advanced or metastatic MTC were enrolled from April to September 2014. The primary endpoint was to evaluate the safety of sorafenib. Treatment efficacy variables including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and maximum reduction in tumor size were evaluated as secondary endpoints. Patients received sorafenib 400 mg orally twice daily on a continuous basis and then continued treatment until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent.ResultsA total of 20 patients were screened, and 18 (8 with MTC and 10 with ATC) were enrolled. The most common drug-related adverse events were palmar-plantar erythrodysesthesia (72%), alopecia (56%), hypertension (56%), and diarrhea (44%). In the ATC patients, median PFS was 2.8 months [confidence interval 0.7-5.6], and median OS was 5.0 months [confidence interval 0.7-5.7]; ORR and DCR were 0% and 40%, respectively. In the MTC population, neither median PFS nor OS had been reached at the time of this analysis; ORR was 25% and DCR was 75%.ConclusionsThe toxicities reported in this study were consistent with the known safety profile of sorafenib. Sorafenib seems to be effective in the treatment of advanced MTC but not ATC, and could be a new treatment option for locally advanced or metastatic MTC and radioactive iodine-refractory DTC.

Project description:BackgroundTyrosine kinase inhibitors (TKIs) have been associated with elevated TSH as a drug class effect. Prior studies of vandetanib in adults with medullary thyroid carcinoma (MTC) described an increase in levothyroxine (LT) requirement. We studied TSH, free T4, and LT dosing in children and adolescents enrolled in the phase I/II trial of vandetanib for medullary thyroid cancer (MTC).MethodsData from 13 patients with multiple endocrine neoplasia type 2B (MEN 2B) and MTC were analyzed [6 M, 7 F, median age 13.0 y (9.1-17.3)] Eleven patients (85%) had undergone prior thyroidectomy and all received single-drug therapy with vandetanib for > 6 months. Confirmed compliance with vandetanib (67-150 mg/m(2)/day) and LT was a necessary inclusion criterion.ResultsWhile on vandetanib treatment, all 11 athyerotic patients exhibited significantly increased TSH levels. The baseline TSH level was 4.37 mclU/ml (0.08 - 23.30); in comparison, the first peak TSH concentration on vandetanib was 15.70 mclU/ml (12.50 - 137.00, p = 0.0010). The median time to reach the initial peak of elevated TSH was 1.8 months (0.3 - 9.3). Free T4 levels remained within the normal reference range. An increase from a baseline LT dose of 91 mcg/m(2)/day (±24) to 116 mcg/m(2)/day (±24) was required in order to resume normative TSH levels (p = 0.00005), equal to an increase of 36.6% (±16.56) in the dosage of LT in mcg/day. For the 2 patients with intact thyroid glands, free T4 and TSH remained normal over a combined 6 patient years of follow up.ConclusionsIn our cohort of pediatric MTC patients, athyreotic patients with preexisting hypothyroidism developed increased TSH and reduced free T4 during the first few months of treatment with vandetanib, necessitating an increase in LT dosage. Additional patients with normal thyroid function before treatment and intact glands (n = 2) maintained normal thyroid function tests during treatment. Elevated TSH in athyreotic patients may be due to an indirect effect of vandetanib on the metabolism of thyroid hormone, or to altered TSH sensitivity at the pituitary. Proper recognition and management of abnormal thyroid hormone levels is critical in growing children on TKIs.Trial registrationClinicalTrials.gov Identifier: NCT00514046.

Dataset Information

Reprogramming of myeloid cells and their progenitors in patients with non-medullary thyroid carcinoma.

Publications

Reprogramming of myeloid cells and their progenitors in patients with non-medullary thyroid carcinoma.

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