How cancer 'trains' your immune system to ignore it

New research published in Science Advances identifies a previously unknown way tumours escape immune surveillance, opening the door to new immunotherapy strategies.

In a discovery that could reshape scientists' understanding of how cancers evade the body's defences, researchers from Japan have found that tumours can manipulate the thymus, the organ responsible for "training" immune cells, to teach the immune system to tolerate cancer instead of attacking it.

The study, led by researchers from Chiba University and published in Science Advances, reveals a previously unknown mechanism through which tumours weaken anti-cancer immunity. The findings also identify a molecule called CCR9 as a promising target for future cancer immunotherapies.

The immune system normally relies on specialised T cells to identify and destroy cancer cells. These T cells are trained in the thymus, where cells that react against the body's own tissues are eliminated to prevent autoimmune disease. Until now, scientists believed that tumours primarily suppressed immunity within the tumour itself and its surrounding microenvironment.

The new study suggests that tumours can influence immune responses much earlier, inside the thymus, by exploiting the body's own mechanism of immune tolerance.

The researchers found that as tumours grow, they recruit specialised immune cells known as plasmacytoid dendritic cells (pDCs). These cells transport tumour-derived antigens from the cancer to the thymus, where they are presented to developing T cells. Because the thymus interprets these antigens as something that should be tolerated, it eliminates T cells capable of recognising and attacking the tumour.

"Our findings suggest that tumours can hijack the physiological machinery of central tolerance to induce systemic immune unresponsiveness against themselves," said Professor Motoko Y. Kimura of Chiba University's Graduate School of Medicine, who led the study.

Using mouse models, the researchers observed that this process begins within two weeks of tumour development and continues as the cancer progresses.

The team identified two distinct populations of plasmacytoid dendritic cells involved in this process. One group transports tumour antigens into the thymus, leading to the deletion of tumour-reactive T cells. The second group produces interferon-alpha, altering the thymic environment and suppressing the production of new T cells, thereby further weakening the body's anti-cancer immune response.

A key finding was the role of CCR9, a chemokine receptor that directs these immune cells to the thymus. When researchers genetically removed CCR9 in mice, the migration of these cells was largely blocked. As a result, the animals retained more cancer-fighting CD8+ T cells and developed significantly smaller tumours.

"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," said first author Dr Yangsong Wang.

"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," he added.

Immune checkpoint inhibitors have transformed the treatment of several cancers over the past decade, but many patients either fail to respond or eventually develop resistance. The researchers believe that preventing tumours from establishing immune tolerance in the thymus could make these therapies more effective.

Beyond cancer, the findings may also have implications for chronic infections. The researchers suggest that long-standing infections that persist in the body might exploit similar thymic tolerance pathways to evade immune attack.

The team says future research will explore therapies that combine existing immune-activating treatments with drugs designed to block this newly identified thymic tolerance pathway, potentially offering a new strategy to strengthen long-term immune responses against cancer and chronic infections.