Metastasis suppression and enhancement of anti-tumour immunity by targeting the FSTL1-DIP2A axis

Cancer immunotherapy, currently a subject of much interest in oncology, has in fact featured in medical literature for centuries. Physicians throughout history noted the coincidence between acute infection and tumour regression, and even used localized infection as rudimentary immunotherapy (1). Whilst today’s clinicians still seek to utilize the body’s natural defence mechanisms to treat cancer, we have become more aware of the challenges involved in immunotherapy. The immune system operates in a state of delicate balance—immune activation must be optimized to detect foreign pathogens whilst avoiding autoimmune attacks on the body’s own tissues. Cancer cells pose a problem for this self/non-self paradigm due to their origin from host tissue. Cancer recognition relies on both sufficient presentation of altered self-antigens by tumour cells, and the detection of such antigens by the immune system. At steady state, such antigens may go undetected as stringent checkpoint mechanisms exist to prevent indiscriminate immune activation. Major checkpoint proteins include cytotoxic T lymphocyte antigen (CTLA-4) and programmed cell death-1 (PD-1), both of which inhibit antigen specific T cell activation. During acute infection, these checkpoints are bypassed and immune cell activation proceeds. This, perhaps, represents the source of historical correlations between infection and regressing tumours—the heightened state of surveillance shifts the balance in favour of a particular antigen being recognized as non-self, thereby enhancing the ability of the immune system to detect cancer