First up: can you describe the aim of your research in 10 words?
To reinvigorate anti-tumour immunity by reprogramming immunosuppressive myeloid cells.
A lot of your work involves haematopoietic cell kinase (HCK). Can you tell me what that is, what you’ve learned about it so far and how it fits into your anti-tumour immunity research?
HCK is a member of the SRC kinase family and is expressed in myeloid cells. Elevated HCK expression is observed in most solid cancers and correlates with poor patient survival.
My research (Poh et al. Cancer Cell 2017, Cancer Immunology Research 2020, Science Advances 2022) is the first to show that aberrant HCK activity promotes gastrointestinal tumour growth in mice by enhancing the immunosuppressive activity of myeloid cells. Immunosuppressive myeloid cells are a major component of solid cancers and play a critical role in tumour development and metastasis by contributing to fibrosis, angiogenesis, immune exhaustion and drug resistance.
My colleagues and I have also shown that genetic ablation or therapeutic inhibition of HCK reduces tumour growth and metastasis in mice by ‘reprogramming’ immunosuppressive myeloid cells towards an immune-stimulatory (inflammatory) endotype. In turn, this reduces tumour fibrosis and angiogenesis, and re-invigorates anti-tumour immunity by enhancing the recruitment and activation of cytotoxic CD8 T-cells and natural killer cells. Importantly, therapeutic HCK inhibition also improves the efficacy of chemotherapy and immunotherapy across a range of tumour types, including stomach, colon, breast and skin cancer. These results are exciting because they demonstrate the broad applicability of HCK as a therapeutic target.
You recently won a grant to explore how targeting HCK in non-small cell lung cancer (NSCLC) can improve therapy responses (congratulations!). Can you tell me a bit about that work?
Up until now, my research has mainly focused on gastrointestinal cancers, but this two-year grant will enable the project to extend laterally into lung cancer so my team and I can identify additional tumour types that may benefit from anti-HCK drugs. We are particularly interested in NSCLC because it is the most common type of lung cancer, and most patients respond poorly to standard-of-care therapy. This is largely attributed to a ‘cold’ tumour microenvironment, which is dominated by immunosuppressive myeloid cells.
The first aim of this project is to establish a strong clinical rationale for developing HCK as a drug target in NSCLC. We will analyse an extensive repository of epidemiological data and patient samples, including clinically-annotated tumour microarrays and fresh tumour biopsies to understand how excessive HCK activation influences local/distant relapse, treatment response and overall prognosis. We are also interested in identifying patient subtypes who are most likely to benefit from anti-HCK drugs in future translational studies.
Our second aim is to validate HCK as an adjuvant therapy to improve the potency of standard-of-care chemotherapies and immunotherapies in orthotopic mouse models of NSCLC. This research complements our ongoing efforts in collaboration with industry partnerships to develop and optimise proprietary small molecule HCK inhibitors with better specificity and efficacy. Further, we’re interested in understanding the immunological mechanisms that underpin reduced tumour growth and enhanced drug synergy following therapeutic inhibition of HCK.
Lots of ground to cover. How did this grant come about and how will it support your research?
The idea for this grant was spurred by initial observations in HCK knock-in mutant mice that have been genetically engineered to express constitutive kinase activity. Approximately 20% of these mice develop lung adenocarcinomas due to excessive lung inflammation, suggesting a link between aberrant HCK activity in myeloid cells and lung cancer.
Because I’m still new to the lung cancer field, I’ve teamed up with Dr Sagun Parkh, who is a consultant medical oncologist and Head of the Lung Oncology Clinic at Austin Health. Dr Parakh is passionate about improving treatment outcomes in lung cancer, and has an amazing track-record in the development and translation of novel therapies into the clinic. We both saw an opportunity to combine our complementary research and clinical expertise to see whether HCK would be a viable therapeutic target in NSCLC.
We are extremely grateful to the Lung Foundation Australia and Cancer Australia for co-funding this project, which will be co-led by myself and Dr Parakh. This grant is invaluable to our development as early-career researchers, and will enable us to purchase critical resources and reagents to continue our work on developing HCK as a drug target in cancer. We will also be supported by an amazing team of clinicians, senior researchers, and consumer advocates to maximise the translational impact of our research.