The immune system plays a critical role in protecting the body from cancer by recognising and eliminating abnormal cells before they can develop into tumours.

This process relies on T cells that can recognise tumour-derived antigens presented by dendritic cells (DCs).

However, tumour cells frequently evade immune surveillance and establish immune tolerance through various mechanisms, most of which are thought to occur within the tumour microenvironment.

In contrast, whether such tolerance is also established in the thymus as central tolerance to tumour antigens remains unclear.

To address this knowledge gap, researchers from Chiba University, Japan, have discovered a mechanism by which tumours can manipulate the thymus, the organ that trains immune cells, to tolerate their presence rather than fight them.

The team was led by Professor Motoko Y. Kimura and first author Dr. Yangsong Wang, both from the Graduate School of Medicine at Chiba University.

The study was published in the journal Science Advances. The thymus is an organ where T cells develop and are trained to distinguish self and non-self.

The study found that as tumours grow, plasmacytoid DCs (pDCs) accumulate in the thymus and help transport tumour antigens there, triggering the elimination of developing T cells capable of recognising tumours.

"Our findings suggest that tumours can hijack the physiological machinery of central tolerance to induce systemic immune unresponsiveness against themselves," says Prof. Kimura.

The team made this discovery by studying tumour-bearing mice, where they observed that pDC accumulation began within 2 weeks of tumour implantation and persisted as the tumours continued to grow.

They found that the migration of pDCs to the thymus is regulated by a chemokine receptor called CCR9.

In mice lacking CCR9, the accumulation of thymic pDCs during tumour progression was largely prevented, indicating that CCR9 is required for this process.

They identified two distinct pDC populations that contribute to this immune evasion. One population originated from common dendritic cell progenitors (CDP-pDCs), while the other arose from common lymphoid progenitors (CLP-pDCs).

CDP-pDCs carry tumour-derived antigens from the tumour to the thymus, where they are presented to developing T cells.

As part of its normal training process, the thymus eliminates T cells that react to these antigens. This removes T cells that could otherwise recognise and attack the tumour, reducing anti-tumour immune responses.

Meanwhile, CLP-pDCs release IFN-α within the thymus, where they alter the thymic environment, suppressing the production of new T cells and further weakening anti-tumour immunity.

Importantly, the researchers found that disrupting CCR9 could interfere with this immune tolerance mechanism.

Mice lacking CCR9 developed smaller tumours and maintained the tumour-specific CD8⁺ T cell population, indicating a stronger anti-tumour immune response.

“Our findings reveal a previously unrecognised mechanism of tumour immune evasion through manipulating thymic function, and identify CCR9 as a potential therapeutic target in cancer immunotherapy. By blocking the migration of tumour antigen-carrying pDCs from tumours to the thymus, it may be possible to enhance anti-tumour immunity and improve responses to existing treatments such as immune checkpoint inhibitors,” says Dr. Wang.

The findings may have implications beyond cancer. The researchers note that chronic or dormant infections that persist in the body for long periods could potentially exploit similar thymic tolerance pathways to evade immune responses.

Looking ahead, the team suggests that future therapies could combine immune-activating treatments with approaches that block thymic tolerance mechanisms.

Such approaches could potentially enhance immune responses against cancer and chronic infections, improving long-term treatment outcomes.

Article: Distinct thymic pDC populations promote tumor immune tolerance through complementary mechanisms

Source: Chiba University