Uncovering the cause of immunotherapy resistance in tumours

In tumour immunotherapy the body’s own defence system is activated against the tumour cells. However, for the majority of patients, the tumour cells eventually become resistant to the treatments used. Researchers at the University of Zurich and the University Hospital Zurich have now found that in the case of skin cutaneous melanoma an epigenetic control protein is key to the development of this resistance.

Tumour immunotherapy holds promise

Cancer is the second most common cause of death worldwide. Until recently, the chances of cure for patients suffering from metastatic cancer were low, as with such cancer the surgical removal of distant metastases in various organs or their local treatment using radiotherapy were usually unsuccessful. Likewise, the use of chemotherapy is limited by its toxic systemic side effects. Tumour immunotherapy has been used for several years, with patients with certain metastatic cancers showing good responses to this treatment.

These immunotherapies – also called checkpoint inhibitors – allow the body’s own immune system to better detect and destroy the cancer cells, however, over time cancer cells become resistant to the triggered immune responses. Now, researchers at the University of Zurich and the University Hospital Zurich have discovered a mechanism that plays a central role in the development of this resistance.

mmune cells fail to detect resistant cancer cells

Cancer cells develop resistance by downregulating the features that immune cells use to detect cancer cells. These include tumour antigen presentation by means of so-called MHC class I molecules. These molecules present tumour-specific peptides on the surface of cancer cells so that they become visible to the immune cells, more specifically to T cells. In addition, cancer cells produce specific immune molecules and trigger immunosuppressive processes. The interaction of these changes makes the cancer cells virtually invisible to the immune cells, whereby the immunotherapy becomes ineffective.

Ezh2 activity blocking proved successful

The team headed up by Onur Boyman, director of the Department of Immunology at the University Hospital Zurich, has now discovered that the epigenetic control protein Ezh2 plays a central role in how cancer cells develop this resistance. Using animal models, the researchers have demonstrated that the tumour mass initially shrinks during treatment of malignant skin cutaneous melanoma with checkpoint inhibitors or immunostimulating interleukin-2 therapy.

Over time, however, the skin cancer cells produced more Ezh2. As a result, the antigen-presenting MHC class I molecules and the antigens specific to skin cutaneous melanoma were suppressed, while the activity of immunosuppressive modules that curb immune cells simultaneously increased. The skin cancer cells became therefore virtually invisible to the immune system and began reproducing in an uncontrolled manner again

"The tumour masses shrank more significantly and the tumour-free survival was extended."

.