Targeting the innate immune stress response to enhance the therapeutic index of radiotherapy
Understanding how tumours exploit innate immune pathways to their advantage, and how we can target these to improve radiotherapy.
An immunosuppressive tumour microenvironment (TME) is a barrier to effective cancer treatment (1). Low oxygen (hypoxia) in the TME is generally considered a driver of immunosuppression and immune evasion (2). In contrast, in response to infection, tissue hypoxia potentiates host inflammatory responses; including innate immunity (3). We hypothesized that investigating innate immune dysregulation in epithelial cancer cells could provide insights into the mechanism allowing tumours to hijack what should normally be productive inflammatory responses. Using this approach, we identified that hypoxia-induced dysregulation of innate immune components of the complement system can drive immune evasion in colon and rectal cancer. Indeed, hypoxia contributes to the increased expression of certain complement proteins in the TME, which in turn, is a phenomenon frequently associated with poor survival outcomes (4).
We have become very interested in this innate immune pathway since cancer cells seem to hijack it for their own survival advantage. Tumours use high complement protein expression to their advantage in a number of ways, including via intracellular expression of complement proteins previously thought to reside exclusively in the extracellular space (5). We have found that once intracellular, complement proteins regulate pro-survival NF-kB signalling, particularly in response to stress. We are exploring the idea that cancer cells may be particularly dependent on these hijacked functions for their survival when exposed to external sources of damage (such as ionising radiation).
Our work to date indeed suggests that, in response to radiotherapy, tumours may be particularly dependent on the functions of dysregulated complement for their survival. Indeed, pharmacological inhibition of certain members of the system can enhance the effects of radiation on the tumour. Intriguingly, our work also indicates that blocking certain members of the complement system can reduce side effects from radiotherapy (6). We are actively investigating the mechanisms underlying these beneficial effects.
Understanding mechanisms allowing tumours to survive and thrive in the TME can help us identify tumour-specific vulnerabilities. Our work has identified complement system dysregulation as one of these vulnerabilities that can be pharmacologically targeted. Importantly, targeting dysregulated complement has the potential to improve the therapeutic window of radiotherapy. This work provides a strong background for future studies aimed at understanding how best to target complement system proteins to improve outcomes of radiotherapy patients.
1. Barker, H. E., Paget, J. T. E., Khan, A. A. & Harrington, K. J. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 15, 409–425 (2015).
2.Olcina M.M., Kim, R.K., Melemenidis, S. Graves E.E., Giaccia, A.J. The tumour microenvironment links complement system dysregulation and hypoxic signalling. Br J Radiol. Accepted March 2018.
3. Palazon, A., Goldrath, A. W., Nizet, V. & Johnson, R. S. HIF transcription factors, inflammation, and immunity. Immunity 41, 518–28 (2014).
4. Olcina, M. M. et al. Mutations in an Innate Immunity Pathway Are Associated with Poor Overall Survival Outcomes and Hypoxic Signaling in Cancer. Cell Rep. 25, 3721-3732.e6 (2018).
5. Olcina, M. M. et al. Intracellular C4BPA Levels Regulate NF-κB-Dependent Apoptosis. iScience 23, (2020).
6. Olcina M.M., Melemenidis S, Nambiar D.K., Kim R.K., Casey K.M., von Eyben R., Woodruff T.M., Graves E.G., Le Q.T., Stucki M., Giaccia A.J. Targeting C5aR1 Increases the Therapeutic Window of Radiotherapy. bioRxiv.