OLCINA GROUP

RESEARCH SUMMARY

The Olcina group is interested in understanding how tumours thrive in immunosuppressive microenvironments, including how they exploit innate immune pathways to their survival advantage. We use this knowledge to identify druggable tumour-specific vulnerabilities to improve tumour response and reduce treatment-induced toxicity.

Specific projects currently being undertaken in the lab include:

1. Investigating mechanisms underlying normal tissue recovery following treatment-induced injury
2. Understanding the causes and consequences of complement system dysregulation in the tumour microenvironment.
3. Understanding and targeting glioma-immune cell interactions in paediatric high-grade glioma (pHGG) to improve immune- and radiotherapy responses - This work is being undertaken as part of the EU-HORIZON HIT-GLIO consortium (more information here).

IMPACT

We have found that to thrive in the immunosuppressive microenvironment tumours mount a stress response characterised by complement system dysregulation. This stress response is also induced following cytotoxic treatments such as radiotherapy, where the complement system is the first immune pathway to be upregulated following treatment. Within the complement system, we have identified that expression of complement C5a receptor 1 (C5aR1) is radiation-inducible and high C5aR1 expression is associated with poor outcome in a number of tumours including glioblastoma and colorectal cancer. Importantly, targeting C5aR1 can improve tumour control following radiotherapy while reducing toxicity, thereby widening the therapeutic window.

REFERENCES

* = Co- corresponding author. + = co-first author.

1. Beach C+, MacLean D+, Majorova D+, Melemenidis S, Nambiar DK, Kim RK, Valbuena GN, Guglietta S, Krieg C, Darvish Damavandi M, Suwa T, Easton A, Hillson LVS, McCulloch AK, McMahon RK, Pennel K, Edwards J, O’Cathail SM, Roxburgh CS, Domingo E, Moon E, Jiang D, Jiang Y, Zhang Q, Koong AC, Woodruff M, Graves EE, Maughan T, Buczacki SJA, Stucki M, Le QT, Leedham SJ, Giaccia AJ and Olcina MM (2023), Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1, J Clin Invest. 

2. Krieg C, Weber LM, Fosso B, Marzano M, Hardiman G, Olcina MM, Domingo E, El Aidy S, Mallah K, Robinson MD, Guglietta S (2022), Complement downregulation promotes and inflammatory signature that renders colorectal cancer susceptible to immunotherapy, J Immunother Cancer.

3. Beach C, MacLean D, Majorova D, Arnold JN, Olcina MM. (2022), The effects of radiation therapy on the macrophage response in cancer, Front Oncol.

4. Bader SB, Ma TS, Simpson CJ, Liang J, Maezono SEB, Olcina MM, Buffa FM, Hammond EM (2021), Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity, Nucleic Acids Res.

5. Olcina MM+*, Balanis NG+, Kim RK, Aksoy BA, Kodysh J, Thompson MJ, Hammerbacher J, Graeber TG, Giaccia AJ* (2018), Mutations in an innate immunity pathway are associated with poor overall survival outcomes and hypoxic signalling in cancer, Cell Reports.

6. Olcina MM and Giaccia AJ (2016), Reducing radiation-induced gastrointestinal toxicity – Role of the PHD/HIF axis. J Clin Invest. 2016 Oct.