TSH/TSHR Signaling Promotes CD8+ T Cell Exhaustion and Immune Evasion in Colorectal Cancer

Background

Colorectal cancer (CRC) is one of the most common malignancies worldwide with high morbidity and mortality rates. Although immune checkpoint blockade (ICB) therapy has shown significant efficacy in some patients, the majority of CRC patients, particularly those with microsatellite stable (MSS) tumors, exhibit poor responses to ICB therapy. The functional exhaustion of CD8+ T cells in the tumor microenvironment (TME) is a critical factor contributing to tumor immune evasion and immunotherapy resistance. While previous studies have shown that hormones such as leptin, steroid hormones, and glucocorticoids can influence T cell function, the role of thyroid-stimulating hormone (TSH) and its receptor (TSHR) in CD8+ T cell exhaustion and tumor immune evasion remains poorly understood.

Source of the Study

This study was conducted by a team of researchers, including Sisi Zeng, Huiling Hu, and Zhiyang Li, from the Department of Pathology at Nanfang Hospital, Southern Medical University. The findings were published on August 13, 2024, in the journal Cancer Communications. The research was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, and the Natural Science Foundation of Guangdong Province.

Research Process and Results

1. Expression of TSHR in Colorectal Cancer

The study began by examining the expression of TSHR in CRC tissues using immunohistochemistry (IHC) and immunofluorescence techniques. The results revealed that TSHR was highly expressed in tumor cells and tumor stromal cells, while its expression was low in normal intestinal epithelial cells and stromal cells. Furthermore, TSHR expression was positively correlated with tumor TNM stage, lymph node metastasis, and distant metastasis.

2. Expression and Function of TSHR in CD8+ T Cells

Using flow cytometry and immunofluorescence, the researchers found that TSHR was highly expressed in CD8+ T cells within CRC tissues but showed low expression in CD4+ T cells. Functional experiments demonstrated that the loss of TSHR significantly reduced the expression of immunosuppressive molecules PD-1 and TIM3 in CD8+ T cells and promoted the production of inflammatory cytokines TNFα and IFNγ. Conversely, overexpression of TSHR increased the expression of PD-1 and CTLA4.

3. TSH/TSHR Signaling Promotes CD8+ T Cell Exhaustion via the PKA/CREB Pathway

RNA sequencing (RNA-seq) analysis revealed that in TSHR-knockout CD8+ T cells, genes associated with T cell exhaustion (e.g., IL-10, CTLA4, PDCD1, HAVCR2) were significantly downregulated, while genes related to T cell effector function (e.g., IL-2, TNF) were upregulated. Further mechanistic studies indicated that TSH/TSHR signaling activates the PKA/CREB pathway, directly regulating the transcription of PD-1 and TIM3.

4. Loss of TSHR Enhances Anti-Tumor Immunity

In mouse models, knockout of TSHR significantly inhibited the growth of CRC, and this effect was dependent on CD8+ T cells. TSHR-knockout CD8+ T cells exhibited stronger anti-tumor activity in the TME, characterized by increased production of TNFα and IFNγ and reduced expression of PD-1 and TIM3.

5. CRC Cells Deliver TSHR Protein via Exosomes

The study found that CRC cells transfer TSHR protein to CD8+ T cells through exosomes, thereby increasing TSHR expression in CD8+ T cells. This process primarily occurs through clathrin-mediated endocytosis and caveolae-mediated endocytosis.

Conclusions and Significance

This study elucidates the mechanism by which TSH/TSHR signaling promotes CD8+ T cell exhaustion and immune evasion in CRC, proposing TSHR as a potential predictive and therapeutic target for CRC immunotherapy. The findings demonstrate that high expression of TSHR in CRC cells and CD8+ T cells promotes CD8+ T cell exhaustion via the PKA/CREB pathway, while the loss of TSHR significantly enhances the anti-tumor activity of CD8+ T cells. Additionally, the discovery that CRC cells transfer TSHR protein via exosomes provides new insights into intercellular communication within the TME.

Research Highlights

1. First to reveal the mechanism by which TSH/TSHR signaling promotes CD8+ T cell exhaustion in CRC, offering a new perspective on tumor immune evasion.
2. Discovered that CRC cells transfer TSHR protein via exosomes, providing a new direction for research on intercellular communication in the TME.
3. Proposed TSHR as a potential predictive and therapeutic target for CRC immunotherapy, offering a theoretical basis for developing new immunotherapeutic strategies.

Additional Valuable Information

The study also employed bioinformatics analysis to show that TSHR expression is positively correlated with T cell exhaustion marker genes (e.g., HAVCR2, PDCD1, CTLA4), further supporting the role of TSHR in CD8+ T cell exhaustion. Moreover, the study validated the function of TSHR in CRC using mouse models, laying the groundwork for subsequent clinical research.

This research not only deepens our understanding of the mechanisms underlying immune evasion in CRC but also provides a critical theoretical and experimental foundation for the development of new immunotherapeutic strategies.