Colorectal cancer (CRC) is a complex disease characterised by intricate interactions between the tumour, the host immune system, and intestinal microbes. Our research has revealed an unexplored aspect of this multifaceted interaction: the presence of FoxP3+ mucosal-associated invariant T cells (MAIT) within human CRC tissue. Remarkably, these FoxP3+ MAIT cells are conspicuously absent in both human non-cancerous colorectal tissue and the peripheral blood of both CRC patients and healthy donors, indicating their unique role in the tumour microenvironment.
We propose that FoxP3 expression in MAIT cells within CRC tissue arises from continuous antigen stimulation. Our investigations have revealed that exposing healthy donor MAIT cells to such stimulation over a mere two-week period is sufficient to induce FoxP3 expression. This intriguing finding sheds light on a potential mechanism responsible for FoxP3 expression in CRC tissue, where the breached mucosal barrier due to the tumour may provide the antigenic stimulus required for FoxP3 induction.
Furthermore, our in vitro studies have demonstrated that FoxP3+ MAIT cells possess immunomodulatory capabilities. They produce soluble anti-inflammatory factors that could play a pivotal role in shaping the CRC immune microenvironment. This phenomenon suggests that FoxP3+ MAIT cells may contribute to the observed lack of inflammatory response within CRC tissue, potentially facilitating tumour immune evasion and progression.
In summary, our findings introduce FoxP3+ MAIT cells as a novel and enigmatic component of the human CRC immune landscape. Their absence in healthy tissues, inducibility in response to antigen stimulation, and immunosuppressive properties suggest a unique role in CRC pathogenesis. Understanding the biology and function of FoxP3+ MAIT cells could open new avenues for therapeutic intervention in CRC by targeting this previously unrecognised factor in the immune microenvironment of CRC.