Modulation of the tumour immune microenvironment by cancer-associated fibroblasts

Abstract

The breast tumour microenvironment (TME) consists of a variety of non-cancerous cell types that can promote or inhibit cancer progression. Cancer-associated fibroblasts (CAFs) represent a major component of the breast TME and are generally considered to have pro-tumourigenic activity through their ability to promote proliferation, invasion, and metastasis of cancer cells. Similarly, immune cells residing within the TME have profound effects upon cancer development, and an appreciation for their role has led to the development of immunotherapies that have revolutionised the treatment of certain cancer types through promotion of anti-tumour immune responses. However, breast cancers remain largely refractory to immunotherapy. One hypothesis for this insensitivity is that the TME protects cancer cells by adopting a highly immunosuppressive state. The overall aim of this PhD project was to better characterise the role of CAFs in modulating the immune microenvironment of breast cancer, with a focus on assessing whether CAFs contribute to immune checkpoint blockade insensitivity. Immune profiling of paired syngeneic mouse mammary carcinoma models, which differ in their CAF content, has revealed how an abundance of CAFs is associated with an immunologically 'cold' immune microenvironment. Characterisation of isolated CAF populations demonstrated an immunomodulatory role for CAFs both in vitro an in vivo. Furthermore, CAF-rich models are insensitive to immune checkpoint blocakde, and transcriptomic and histopathological analysis identified a link between stromal activation and an immune excluded tumour phenotype. Finally, alteration of CAFs, either through genetic deletion of CAF-restricted receptors, or epigenetic modulation, has provided new insights into CAF-induced immunosuppression and identified possible novel CAF-associated approaches to enhancing the sensitivity of breast cancer to immune checkpoint blockade.