ANAPLASTIC THYROID CANCER CELL-SECRETED TGFB-1 INDUCES M2-LIKE MACROPHAGE POLARIZATION OF HUMAN MONOCYTES

GEYSELS, ROMINA CELESTE; BRAICA, MARIA VICTORIA; BRUGO, MARIA BELEN; PELLIZAS, CLAUDIA G.; NICOLA, JUAN PABLO; CHENG, SHEUE-YANN ; FOZZATTI, LAURA

Curitiba

Congreso; XIX Latin American Thyroid Congress; 2023

Sociedad Latinoamericana de Tiroides

Introduction: Anaplastic thyroid cancer (ATC) is a clinically aggressive form of undifferentiated thyroid cancer with limited treatmentoptions. Tumor-associated macrophages (TAMs) constitute over 50% of ATC-infiltrating cells, and their presence is associated witha poor prognosis. The mechanisms of how TAMs promote ATC progression are not clear. We have previously shown that solublefactors secreted by ATC cells induced pro-tumor M2-like polarization of THP-1 cells (human monocytes). However, it remains tobe identified which ATC cell-derived soluble factors drive macrophage activation. Objective: To investigate the effect of ATC cellderived transforming growth factor β1 (TGF-β1) on macrophage phenotype. Methods: THP-1 cells (human monocytes) were treatedwith human ATC cell lines 8505C or C643-derived conditioned media (ATC-CM) or recombinant human TGF-β1 protein. THP-1cell proliferation and polarization were assessed by flow cytometry, RT-qPCR and Western blot analysis. TGF-β1 levels in ATC-CMwere quantified by ELISA. Gene expression profiles were obtained from the NCBI Gene Expression Omnibus database and analyzedusing bioinformatics analysis. Results: Similar to our previous studies using ATC-CM, TGF-β1 treatment significantly influencedthe phenotype of THP-1 cells. The changes involved increased expression of CD163 and CLEC7A, which are classic M2 phenotypemarkers of TAMs. In contrast, the levels of CCL13, another M2 marker, were decreased. TGF-β1 treatment decreased the proliferationof THP-1 cells and increased the mRNA expression of the pro-inflammatory cytokine IL-6. Moreover, we showed that TGF-β1induced mRNA and protein levels of the transcription factors SNAIL and SLUG. Accordingly, TGF-β1 was detected in ATC-CM(DMEM, 10.42 ± 5.4 pg/mL; 8505C cell-derived CM, 3251 ± 162.5 pg/mL; C643 cell-derived CM, 2752 ± 213.1 pg/mL). We validatedthe clinical significance of the expression of TGF-β ligands and its receptors in human ATC by analyzing public microarray datasets,and found that the expression of TGF-β ligands as well as their receptors were significantly higher in human ATC tissue samples than innormal thyroid tissues. Conclusions: Our findings indicate that ATC cell-secreted TGF-β1 may play a key role in M2-like macrophagepolarization of human monocytes possible involving the up-regulation of SNAIL and SLUG transcription factors. Thus, ours resultsuncovered a novel mechanism involved in the activation of TAMs by soluble factors released by ATC cells. Our findings have providednovel rationale basis for the development of original therapies for ATC.