Developing Therapeutic Approaches to Enhance Tumour-Specific Immunity in Breast Cancer

Abstract

Immunotherapy has proven capable of delivering unheralded clinical benefit in many cancers, resulting in a transformation in research and treatment approaches. However, many challenges remain. Currently, immunotherapy only provides significant benefit in immunogenic tumours, and is only efficacious in a minority of patients. Research efforts are therefore focused on improving tumour immunogenicity in less immunogenic tumours such as breast cancer. Triple negative breast cancer (TNBC) has a poor prognosis, but may also have potential for generation of a robust anti-tumour immune response. Epigenetic alterations in anti-tumour immunity are thought to contribute to reduced immunogenicity; treatment with epigenetic agents including histone deacetylase inhibitors (HDACi) could therefore restore robust anti-tumour immunity through an immune priming effect. It was therefore hypothesised that HDACi could induce immune changes in TNBC leading to an effective anti-tumour immune response. To investigate this, a 4T1 orthotopic murine model was developed and characterised. A progressive systemic myeloid infiltrate was noted in the tumour microenvironment and systemic organs, alongside development of lung metastases. 4T1 cells released pro-myeloid cytokines in vitro, suggesting that increasing myeloid infiltration was likely driven by cytokines released by tumour cells in vivo. Treatment of the 4T1 model with the HDACi entinostat led to a non-statistically significant decrease in tumour volume and a trend towards reduction in lung metastatic burden. Since no entinostat-induced overall changes to immune cell population frequencies were detected, it was hypothesised that functional changes could be more important to treatment outcomes. Entinostat was able to reduce immunosuppressive function of CD11b+ cells within the spleen. However, there was also a suggestion that entinostat could increase the immunosuppressive function of CD11b+ cells within the lung. Combination therapy with entinostat and radiation revealed that single agent radiation could delay tumour growth but did not result in long-term tumour control or control of metastatic disease. Importantly, addition of entinostat to single dose, but not fractionated radiation, enhanced outcomes in this radio-resistant tumour model. Fractionated radiation led to increases in myeloid derived suppressor cells (MDSCs), particularly in the spleen. Addition of entinostat to fractionated radiation led to further increases in some MDSC populations. These data suggest that entinostat delivered either as monotherapy, or in combination with radiation, can alter the immune landscape. This has important implications for combination with other immunomodulatory therapies in future studies, to achieve maximum translational relevance and ensure that the potential of HDACi therapy can be realised.

Date of Award	31 Dec 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Anne Armstrong (Supervisor) & Jamie Honeychurch (Supervisor)