Epigenetics – A double-edged sword to fight Cancer

Cancer Immunotherapy is rapidly becoming a clinical reality. Gearing the host’s own immune system to target and kill cancerous cells would provide a potent therapy, capable of not only targeting cancer cells with efficiency and accuracy, but attacking them with memory. Just as vaccination therapy provides memory against foreign protein sequences of diseases, termed antigens, so too could cancer immunotherapy prime the immune system to recognise ‘antigens’ characteristic of cancer cells. This form of therapy would allow re-occurring cancers to be persistently targeted with immunological memory, one of the greatest dilemmas in oncology. Our rapidly developing knowledge of the immune system parallels the growing diversity of potential immunotherapies, but when combined with a relatively new area of clinical pharmacology, ‘epigenetics’, we may be able to prime immunotherapies to overcome their therapeutic setbacks.

 

Adoptive cell therapy (ACT) uses microinjected cancer fighting, ‘cytotoxic’ T cells that are primed to recognise and invade tumor cells. In the majority of cases, tumors are capable of evading attack by the injected cytotoxic T cells. Tumor cells employ ‘epigenetic’ mechanisms that reduce the activity of genes that produce tumor-associated molecules on cancer cell surfaces, that would otherwise be targetable during adoptive cell therapy. T cells target tumor-associated-antigens as well as co-stimulatory molecules that increase the tumor-targeting potential of T cells and other immune effectors. When cells become malignant, they deploy ‘epigenetic’ mechanisms that fine-tune the structure of their DNA to reduce the level of tumor-associated-antigens, HLA class-1, calnexin and calreticulin molecules on their cell surface. Ultimately, as cancer cells progress, they reduce the amount of immunostimulatory molecules on their cell surface, reducing the ability of immune cells to interact and kill malignant cells. Evasive and unimpeded by the host immune system, tumor cells can therefore progress to more malignant stages of the disease.

As cancer cells progress, they reduce the amount of immunostimulatory molecules on their cell surface, reducing the ability of immune cells to interact and kill malignant cells.

However, our inventory against tumor immunoevasion is rapidly developing. In understanding the mechanism by which cancer cells use ‘epigenetic’ strategies to alter the immunostimulatory molecules on their cell surface, we can produce drugs that are preventative of cancer immune evasion. When genes become active, their ultrastructure within the nucleus must be accessible to proteins (polymerases and cofactors) that permit the gene’s activity. Usually coiled in the nucleus, genes become active by uncoiling, or shifting from a state termed ‘heterochromatin’ to ‘euchromatin’. The enzymes responsible for transitioning between these two ‘off’ and ‘on’ states are called DNA methyltransferases and Histone Deacetylases. They work by adding methyl groups or removing acetyl groups to DNA, closing and opening the DNA structure respectively. Cancer cells use these enzymes to alter their DNA structure and restrict the expression of tumor-associated-antigens, such as HLA class-1 molecules, ICAM-1 and CD80/CD86.

 

By using the same principle that tumors use to evade the immune system, we are now developing drugs that alter epigenetic processes to prime tumor cells to become more visible to the immune system. DNA methyltransferase inhibitors (DMNTi) and Histone Deacetylase inhibitors (HDACi) can be delivered to the tumor microenvironment, where they alter the activity of epigenetic enzymes. The epigenetic drugs inhibit the modification of the DNA ultrastructure by epigenetic enzymes, increasing the amount of immune signaling molecules on the surface of cancer cells. When used in tandem with immunotherapies, these epigenetic drugs prime tumor cells to be targeted by the immunotherapy itself, allowing immune cells to target the tumor with greater accuracy and affinity – a double-edged sword in the fight against cancer.

 

Robust data supports this combined approach to immunotherapy. Dual epigenetic therapy with azacytidine and entinostate, a HDACi that upregulates the T cell target cell-surface molecule HLA-class-1 in tumors has shown promising results. Five out of six patients in the trial survived six months post-treatment without cancer progression. To combat the concerns that epigenetic drugs may have a short half-life and are sensitive to deactivation, second generation drugs such as guadecitabine are currently in development.

When used in tandem with immunotherapies, these epigenetic drugs prime tumor cells to be targeted by the immunotherapy itself, allowing immune cells to target the tumor with greater accuracy and affinity – a double-edged sword in the fight against cancer.

Although in its therapeutic infancy, epigenetic therapy shows great promise. Re-educating tumor cells to become sensitive to immune attack via epigenetic therapies is a promising tool for the future of cancer treatment, which may become standardized as a priming technique when used in combination with existing cancer therapies. As with any anti-cancer therapy, more widespread trials are needed to continue the progress we’re currently making.

 

References

  1. J. Dunn, S. Rao – Epigenetics and immunotherapy: The current state of play. Molecular Immunology 87 (2017) 227-239.
  2. Chiappinelli, K.B., Zahnow, C.A., Ahuja, N., Baylin, S.B. Combining epigenetic and immunotherapy to combat cancer. Cancer Res. (2016) 76, 1683–1689.
  3. Larkin, J et al – Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. (2015) N. Engl. J. Med. 373, 23–34.
  4. Tellez, C.S., Grimes, M.J et al., – SGI-110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome. Int. J. Cancer (2014) 135, 2223–2231.