Breakthrough in oncology: new approach makes breast cancer sensitive to immunotherapy

This subtype accounts for about 70% of all breast cancers, and it is the subtype that accounts for the highest number of deaths overall, despite the availability of effective hormone therapy and targeted therapies.

Until now, immunotherapy for these tumours has hardly worked or even been approved for use except in a small group of patients with low estrogen receptor levels. The new work, published in the Journal of Clinical Investigation, shows a way to 'light up' these tumours for the immune system and make them vulnerable to immune attacks.

How the estrogen receptor helps tumours hide

The study authors analysed open data from clinical trials and showed: the estrogen receptor plays a key role in the tumour's strategy to evade the immune response. Its activity restricts immune cells from entering the tumour and makes immunotherapy ineffective.

When the estrogen receptor is blocked, however, the LCOR and interferon signalling pathways are activated, factors associated with the mechanisms of antigen presentation on the cell surface. In other words, the tumour cell becomes more 'visible' to the immune system.

The team went on to create a preclinical animal model, confirming this protective mechanism. They also found that the molecule LCOR, which in previous experiments on triple-negative breast cancer enhanced the effect of immunotherapy, is literally "hijacked" by the estrogen receptor in luminal tumours and cannot fully function.

"The estrogen receptor binds LCOR and prevents it from activating the antigen-presenting system, which leaves the tumour invisible to the immune system," explains the leader of the work, Dr Toni Sella-Terraza, coordinator of the Laboratory of Cancer Stem Cells and Metastasis Dynamics at Hospital del Mar Research Institute.

Two strategies to make the tumour visible

To circumvent this mechanism, the researchers tested two strategies in preclinical models.

1. A combination of hormone therapy, LCOR and immunotherapy.
   LCOR and immunotherapy were combined with estrogen receptor inhibitors (endocrine therapy), which are already used to treat luminal breast cancer.
   "Normally, estrogen signalling is dominant and prevents LCOR from exhibiting its functions. If we disrupt this signalling with anti-estrogen therapy, LCOR activates antigen presentation and opens the way for immunotherapy," explains researcher José Ángel Palomeque.

2. Creating a modified version of LCOR.
   The scientists developed a modified form of the protein, LCOR LSKAA, which can no longer bind to the estrogen receptor. This modification allows LCOR to "escape" the blocking influence of the receptor and more effectively switch on the mechanisms needed to attack the immune system.

Hospital del Mar's RNAi Therapeutics Laboratory is already utilising these developments, creating experimental versions of modified LCOR in an RNAi therapeutics format in combination with immunotherapy. A separate spin-off project by VIOLET Pharmaceuticals will develop similar approaches in the form of future drugs.

What this means for female patients

According to Dr João Albanel, head of oncology at Mar Hospital and director of the institute's oncology programme, the study "opens the door to a new strategy to make this subtype of breast cancer sensitive to immunotherapy".

The team's goal is to turn the modified LCOR into a complete therapy that can be tested in clinical trials in patients with estrogen-positive tumours. Right now, it is the presence of estrogen receptors that effectively "turns off" immunotherapy for most such patients.