Title: Myeloid cell phagocytosis mediates innate immune training-dependent tumour suppression
Funder: The Academy of Medical Sciences

Abstract: More than nine million deaths worldwide were linked to cancer in 2018, representing the second leading cause of death and having long-lasting socioeconomic impact. There is an increasing need to better understand disease pathogenesis to inform the development of therapeutic approaches and to address the timely question of how to increase the efficacy of current immunotherapies. Myeloid cells in solid tumours display hallmarks of cancer and have been described as a major component in shaping the balance between pro-tumour and anti-tumour responses. The hallmark effector function of myeloid cell phagocytosis has been also implicated in regulating anti-tumour immunity. Innate immune training (IIT) mediates sustained increased responsiveness to homologous or heterologous secondary challenges via modulation of myeloid cells. My research has contributed to the better understanding of phagocytosis-mediated disease resolution and IIT-dependent tumour suppression. Building upon my previous experience and on my preliminary data in the study of tumour cell phagocytosis, I aim to investigate IIT mechanisms that mediate myeloid cell-dependent tumour suppression through phagocytosis. Utilisation of cutting-edge microscopy techniques, computational image analysis and in vivo tumour models will allow the characterisation of tumour cell-myeloid cell interactions. To better ensure my findings are translatable to humans, I will use xenograft models to evaluate the ability of ‘trained’ human myeloid cells to phagocytose tumour cells and thereby suppress tumour growth. Together, this research aims to identify novel mechanisms of myeloid cell-dependent tumour suppression and may set the stage for designing new cellular immunotherapeutic approaches.

Lay abstract: Cancer represents the second leading cause of death worldwide and has immense socioeconomic impact. A subset of white blood cells (called myeloid cells) is a major component of our immune system and are typically able to recognise, kill and remove ‘foreign’ material, including tumour cells (a process known as phagocytosis). However, tumour cells have developed ways to evade the immune system, exploit myeloid cell functions and compromise anti-tumour responses. Therefore, strategies that aim to educate the immune system for enhanced tumour killing need to be developed. Exposure of the host to certain types of stimuli induces a type of memory in myeloid cells termed innate immune training (IIT) that subsequently affects their responses upon secondary re-stimulation. How IIT modulates phagocytosis in tumours is completely unknown. I aim to examine how IIT in myeloid cells alters anti-tumour immune responses. I hypothesize that IIT promotes tumour cell clearance by myeloid cell phagocytosis. To test this, I will assess myeloid cell–tumour cell interactions and use genetically altered mice that allow the study of anti-tumour immune responses using human cells. Together, the research will provide better understanding of mechanisms that may boost our immune system to fight cancer thus setting the stage for designing improved or new anti-cancer drugs and treatments.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS