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.

Emerging therapeutic options for follicular-derived thyroid cancer in the era of immunotherapy

“…While TAMs compose a smaller percentage of the total cells in PTC, they tend to be positively associated with more aggressive pathologies such as larger tumor sizes and lymph node metastasis ( 91 ). Compared to PTCs, the ATC TME is characterized by a polarization toward M2 macrophages (SELENOP+, SPP1+MARCO+, and SPP1+TGFBI+) and a decrease in M1 macrophages (IL-1B+, FCGBP+, and TXNIP+) ( 68 , 83 , 92 – 94 ). Soluble factors produced by ATC cells induce pro-tumor M2-like polarization of monocytes through T-cell immunoglobulin and mucin-domain containing protein-3 (TIM3).…”

“…Soluble factors produced by ATC cells induce pro-tumor M2-like polarization of monocytes through T-cell immunoglobulin and mucin-domain containing protein-3 (TIM3). TIM3 and CSF1R expression as well as several pathways, such as E2F targets, IL-6-JAK-STAT3, and G2M checkpoint are positively correlated with the TAM-related prognostic index and T cell dysfunction in ATC ( 94 ). FZD6, RBBP8, PREX1 and HSD3B7 expressed by M2 macrophages are prognostic factors that are correlated with proliferation and invasion of ATC ( 95 , 96 ).…”

TIM-3 as a promising target for cancer immunotherapy in a wide range of tumors

“…In medullary thyroid carcinomas, expression of TIM-3, CTLA-4, and coexpression of PD-1/PD-L1 are related to poorer structural recurrence-free survival [ 71 ]. In thyroid tumors, a significant effect was observed on tumor-associated macrophages (TAM), where induction of their activation toward a pro-cancer phenotype was observed along with elevation of the checkpoint marker TIM-3 [ 72 ]. It was confirmed that TIM-3 induces tumor-promoting M2-like macrophage polarization [ 70 ].…”

“…It was confirmed that TIM-3 induces tumor-promoting M2-like macrophage polarization [ 70 ]. Interestingly, experiments using TIM-3-blocking antibodies partly reversed these effects, suggesting a role for this receptor in the activation and pro-tumorigenic effects of TAMs in thyroid cancer in vitro [ 72 ]. In the study by Pani et al, analysis performed within the thyroidal immune infiltrate revealed that anti-TIM-3 treatment was associated with a significant change in the expression of 9167 genes compared to animals treated with isotype control [ 73 ].…”

X-ray cross-complementing family: the bridge linking DNA damage repair and cancer

“…Unlike targeted therapy, which focuses on specific targets, immunotherapy eliminates tumour cells by activating the body’s immune system and utilising immunoactive substances and immune cells produced by the body [ 82 , 83 ]. Several immune checkpoints associated with tumour immunity have been identified, including cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), T-cell immunoglobulin and mucin-domain containing protein-3 (TIM3), and lymphocyte activating 3 (LAG3), among others [ 84 – 87 ]. Damaged DNA repair and associated genomic instability not only elevate mutagenicity and oncogenicity but also augment the neoantigenic load on the surface of tumour cells, thereby increasing their immunogenicity [ 88 , 89 ].…”