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TIM3 Expression in Anaplastic-Thyroid-Cancer-Infiltrating Macrophages: An Emerging Immunotherapeutic Target.

ABSTRACT: Anaplastic thyroid cancer (ATC) is a clinically aggressive form of undifferentiated thyroid cancer with limited treatment options. Immunotherapy for patients with ATC remains challenging. Tumor-associated macrophages (TAMs) constitute over 50% of ATC-infiltrating cells, and their presence is associated with a poor prognosis. Consequently, the development of new therapies targeting immune checkpoints in TAMs is considered a promising therapeutic approach for ATC. We have previously shown that soluble factors secreted by ATC cells induced pro-tumor M2-like polarization of human monocytes by upregulating the levels of the inhibitory receptor TIM3. Here, we extended our observations on ATC-cell-induced xenograft tumors. We observed a large number of immune cells infiltrating the ATC xenograft tumors. Significantly, 24-28% of CD45⁺ immune cells were macrophages (CD11b⁺ F4/80⁺). We further showed that 40% of macrophages were polarized toward a M2-like phenotype, as assessed by CD206 expression and by a significant increase in the Arg1/iNOS (M2/M1) ratio. Additionally, we found that ATC xenograft tumors had levels of TIM3 expression when determined by RT-PCR and immunofluorescence assays. Interestingly, we detected the expression of TIM3 in macrophages in ATC tumors by flow cytometry assays. Furthermore, TIM3 expression correlated with macrophage marker expression in human ATC. Our studies show that TIM3 is a newly identified immune checkpoint in macrophages. Since TIM3 is known as a negative immune regulator, it should be considered as a promising immunotherapeutic target for ATC.

SUBMITTER: Palacios LM

PROVIDER: S-EPMC9687546 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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TIM3 Expression in Anaplastic-Thyroid-Cancer-Infiltrating Macrophages: An Emerging Immunotherapeutic Target.

Palacios Luz Maria LM Peyret Victoria V Viano María Estefania ME Geysels Romina Celeste RC Chocobar Yair Aron YA Volpini Ximena X Pellizas Claudia Gabriela CG Nicola Juan Pablo JP Motran Claudia Cristina CC Rodriguez-Galan María Cecilia MC Fozzatti Laura L

Biology 20221103 11

Anaplastic thyroid cancer (ATC) is a clinically aggressive form of undifferentiated thyroid cancer with limited treatment options. Immunotherapy for patients with ATC remains challenging. Tumor-associated macrophages (TAMs) constitute over 50% of ATC-infiltrating cells, and their presence is associated with a poor prognosis. Consequently, the development of new therapies targeting immune checkpoints in TAMs is considered a promising therapeutic approach for ATC. We have previously shown that sol ...[more]

PMID: 36358310

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Project description:Background: Anaplastic thyroid cancer (ATC) is a rare cancer with poor prognosis and few treatment options. The objective of this study was to investigate new immune-associated therapeutic targets by identifying ATC-derived, human leukocyte antigen (HLA) class II-presenting peptides. One protein that generated multiple peptides in ATC was chondroitin sulfate-proteoglycan-4 (CSPG4), a transmembrane proteoglycan with increased expression in multiple aggressive cancers, but not yet investigated in ATC. Methods: We applied autologous peripheral blood T cells to ATC patient-derived xenografted mice to examine whether ATC induces a tumor-specific T cell response. We then identified peptide antigens eluted from the HLA-DQ complex in ATC patient-derived cells using mass spectrometry, detecting abundant CSPG4-derived peptides specific to the ATC sample. Next, we analyzed the surface expression level of CSPG4 in thyroid cancer cell lines and primary cell culture using flow cytometry. In addition, we used immunohistochemistry to compare the expression level and localization of the CSPG4 protein in ATC, papillary thyroid cancer, and normal thyroid tissue. We then investigated the correlation between CSPG4 expression and clinicopathological features of patients with thyroid cancer. Results: We found that ATC tissue had a high level of HLA-DQ expression and that the patient's CD4+ T cells showed activation when exposed to ATC. By eluting the HLA-DQ complex of ATC tissue, we found that CSPG4 generated one of the most abundant and specific peptides. CSPG4 expression at the cell surface of thyroid cancer was also significantly high when determined by flow cytometry, with the majority of ATC cell lines exhibiting ∼10-fold higher mean fluorescence intensity. Furthermore, most ATC patient cases expressed CSPG4 in the cytoplasm or membrane of the tumor cells. CSPG4 expression was correlated with tumor size, extrathyroidal extension, and intercellular adhesion molecule-1 (ICAM-1) circumferential expression. CSPG4 mRNA overexpression was associated with worse overall survival in patients with ATC and poorly differentiated thyroid cancer. Conclusions: CSPG4 expression is significantly elevated in aggressive thyroid cancers, with a strong correlation with a poor prognosis. The vast number of HLA-DQ eluted CSPG4 peptides was identified in ATC, demonstrating the potential of CSPG4 as a novel immunotherapeutic target for ATC.

Dataset Information

TIM3 Expression in Anaplastic-Thyroid-Cancer-Infiltrating Macrophages: An Emerging Immunotherapeutic Target.

Publications

TIM3 Expression in Anaplastic-Thyroid-Cancer-Infiltrating Macrophages: An Emerging Immunotherapeutic Target.

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