The Role of TDO2 Inhibition in Lung Cancer Immune Evasion

Background Introduction

Lung cancer is one of the leading causes of cancer-related deaths worldwide, with smoking recognized as a primary cause of its occurrence. Cigarette smoke contains numerous carcinogens, among which benzo[a]pyrene (BAP), a polycyclic aromatic hydrocarbon, has been shown to promote the development and progression of lung cancer by activating the aryl hydrocarbon receptor (AHR). In recent years, the role of immune checkpoint molecules such as PD-L1 (programmed death-ligand 1) in tumor immune evasion has garnered significant attention. PD-L1 binds to PD-1 on the surface of T cells, inhibiting their activity and thereby helping tumor cells evade immune system attacks. Although PD-L1/PD-1 blockade therapy has shown remarkable clinical efficacy in lung cancer treatment, the mechanisms by which environmental carcinogens like BAP promote immune evasion through immune checkpoint molecules remain unclear.

Additionally, the role of tryptophan (Trp) metabolism in tumor immune evasion has gradually been uncovered. Tryptophan is metabolized by IDO1 (indoleamine 2,3-dioxygenase 1) and TDO2 (tryptophan 2,3-dioxygenase) into kynurenine (Kyn), which serves as an endogenous ligand for AHR. Activation of AHR can promote the generation of regulatory T cells (Tregs), thereby suppressing anti-tumor immune responses. However, whether BAP induces immune evasion through the tryptophan metabolism pathway and the specific role of TDO2 in this process require further investigation.

Source of the Paper

This paper was co-authored by Isa Taş, Mücahit Varlı, Sultan Pulat, Hyun Bo Sim, Jong-Jin Kim, and Hangun Kim, affiliated with the College of Pharmacy and the Department of Biomedical Science at Sunchon National University, South Korea. The study was published in 2024 in the journal Cancer & Metabolism, titled “TDO2 inhibition counters benzo[a]pyrene-induced immune evasion and suppresses tumorigenesis in lung adenocarcinoma”. The research was supported by funding from the National Research Foundation of Korea.

Research Process and Results

1. BAP Induces Immune Checkpoint Molecule Expression

The study first examined the effects of BAP on the expression of immune checkpoint molecules PD-L1 and ICOSL (inducible T-cell co-stimulator ligand) in lung cancer cell lines (BEAS-2B and H1975). The results showed that BAP significantly upregulated the mRNA and surface protein expression of PD-L1 and ICOSL. Flow cytometry analysis revealed that BAP increased the surface expression of PD-L1 and ICOSL in a dose-dependent manner. This indicates that BAP enhances the immune evasion ability of lung cancer cells by inducing the expression of multiple immune checkpoint molecules.

2. Role of AHR in BAP-Induced Immune Checkpoint Expression

To investigate the role of AHR in BAP-induced immune checkpoint expression, the researchers silenced AHR expression using siRNA. The results showed that AHR silencing significantly suppressed BAP-induced PD-L1 and ICOSL expression. This suggests that AHR plays a critical role in BAP-mediated immune evasion.

3. Role of Tryptophan Metabolism in BAP-Induced Immune Evasion

The researchers further explored the role of tryptophan metabolism in BAP-induced immune evasion. By culturing cells under different tryptophan conditions, they found that BAP significantly increased PD-L1 and ICOSL expression in tryptophan-sufficient conditions, whereas this induction was completely or partially inhibited in tryptophan-deficient conditions. Additionally, BAP upregulated the expression of tryptophan metabolism-related genes, such as TDO2 and IDO1. These results indicate that tryptophan metabolism, through AHR activation, participates in BAP-mediated immune evasion.

4. Effects of TDO2 Inhibition on Immune Checkpoint Expression

To further investigate the roles of TDO2 and IDO1 in BAP-induced immune checkpoint expression, the researchers used the TDO2 inhibitor 680C91 and the IDO1 inhibitor Epacadostat. The results showed that the TDO2 inhibitor significantly suppressed BAP-induced PD-L1 and ICOSL expression, whereas the IDO1 inhibitor had no significant effect. This suggests that TDO2 plays a key role in BAP-mediated immune evasion.

5. Expression of TDO2 in Lung Cancer Patients and Its Association with Prognosis

By analyzing the GEPIA and UALCAN databases, the researchers found that TDO2 expression was significantly higher in lung adenocarcinoma (LUAD) tissues compared to normal lung tissues, while IDO1 expression showed no significant difference. Furthermore, high TDO2 expression was significantly associated with poor prognosis in LUAD patients. This further supports the potential of TDO2 as a therapeutic target for LUAD.

6. Anti-Tumor Effects of TDO2 Inhibition in Lung Cancer Models

To evaluate the therapeutic potential of TDO2 inhibition, the researchers conducted an orthotopic lung cancer model experiment in C57BL/6 mice. The results showed that TDO2 inhibitors 680C91 and LM10 significantly suppressed tumor growth without causing significant toxicity. Additionally, TDO2 inhibitors significantly reduced the expression of immune checkpoint molecules and Treg markers in tumor tissues. These results indicate that TDO2 inhibition can effectively enhance anti-tumor immune responses.

Conclusions and Significance

This study reveals the mechanism by which BAP induces immune evasion in lung adenocarcinoma through the TDO2/AHR axis and demonstrates the potential of TDO2 inhibitors in suppressing tumor growth and enhancing anti-tumor immune responses. This discovery provides new insights for immunotherapy in lung adenocarcinoma, particularly targeting TDO2. Furthermore, the study highlights the important role of environmental carcinogens in tumor immune evasion, offering a theoretical basis for future cancer prevention and treatment.

Research Highlights

1. Mechanistic Innovation: First to reveal the mechanism by which BAP induces immune evasion in lung adenocarcinoma through the TDO2/AHR axis.
2. Therapeutic Potential: Demonstrates the potential of TDO2 inhibitors in lung adenocarcinoma treatment, providing a basis for developing new immunotherapy strategies.
3. Clinical Relevance: Database analysis shows that high TDO2 expression is associated with poor prognosis in LUAD patients, further supporting its importance as a therapeutic target.

Additional Valuable Information

The study also provides detailed experimental methods and data analysis procedures, including siRNA interference experiments, quantitative RT-qPCR, Western blotting, and flow cytometry. These methods serve as references for future related research. Additionally, the study utilized multiple lung cancer cell lines and mouse models, ensuring the reliability and broad applicability of the results.

This research not only deepens our understanding of the immune evasion mechanisms in lung adenocarcinoma but also provides important experimental evidence for the development of new immunotherapy strategies.