The Impact of Inflammation-Driven Cancers on Immune Ageing

Research Opportunity
PhD, Masters by Research
Department
Medicine and Radiology
Location
Royal Melbourne Hospital
Primary Supervisor Email Number Webpage
Prof David Ritchie david.ritchie@mh.org.au 8559 7262 Personal web page
Co-supervisor Email Number Webpage
Dr Rachel Koldej rachel.koldej@mh.org.au 8559 7264 Personal web page
Dr Kylie Quinn kylie.quinn@rmit.edu.au +61-459113738

Summary Chronic inflammation can accelerate cellular ageing, particularly in immune cells, and certain forms of cancer can be highly inflammatory. This project aims to dissect the signalling pathways induced by multiple myeloma-driven inflammation in immune cells and to identify targets for preserving immune function in cancer patients.

Project Details

As we get older, our immune cells become less functional, which can leave us vulnerable to infections and cancer [1]. A number of mechanisms can accelerate biological ageing, including DNA damage, disruption to proteostasis, chronic inflammation and increased metabolic load (reviewed in [2]). Of note, some cancers such as multiple myeloma and their conventional treatments are predicted to augment these mechanisms of ageing.  MM disease itself is inflammatory, with increased circulating levels of IL-6 correlating with poorer prognosis [3]. Conventional treatment for MM involves a rigorous course of corticosteroids, immune modulatory drugs, protease inhibitors, alkylating agents, chemotherapy and autologous stem cell transplants (ASCT) [4]. While some of these treatments may reduce MM-associated inflammation (corticosteroids, lenalidomide), other treatments could promote ageing by disrupting proteostasis (protease inhibitors), causing DNA damage (alkylating agents) or increasing metabolic load on immune cells during lymphopenia (ASCT).

Indeed, we have observed signs of accelerated immune ageing with MM disease and treatment. There are fewer CD8 TN cells in newly diagnosed MM patients, there are fewer CD4 and CD8 TN cells after treatment [5] and there is evidence of significant metabolic stress after ASCT. All of this is consistent with accelerated immune ageing and we predict that it will lead to loss of immune function. In addition, a new treatment is being developed for MM, called chimeric antigen receptor (CAR) T cell therapy. This therapy relies on access to highly functional T cells from the patient and we predict that MM disease and treatments may limit the efficacy of CAR T cell therapy.

This project aims to dissect immune ageing over the course of MM disease and treatment by:

  • Monitoring CD4 and CD8 T cell function, in terms of proliferation, cytokine production and cytotoxicity;
  • Assessing the efficacy of the CAR T cell therapy in vitro protocol;
  • Identifying novel biomarkers of immune ageing;
  • Tracking transcriptional changes in T cells that correlate with immune ageing phenotypes and loss of function.

References:

[1] Goronzy JJ, Weyand CM. Mechanisms underlying T cell ageing. 2019, Nat Rev Immunol, doi: 10.1038/s41577-019-0180-1 (Epub ahead of print)
[2] López-Otín C, Blasco MA, Partridge L, et al. The hallmarks of aging. 2013, Cell, 153, p1194-217.
[3] Ludwig H, Nachbaur DM, Fritz E, et al. Interleukin-6 is a prognostic factor in multiple myeloma. 1991, Blood, 77, p2794-2795.
[4] Rajkumar SV, Kumar S. Multiple Myeloma: Diagnosis and Treatment. 2016, Mayo Clin Proc, 91, p101-119.
[5] Cooke RE, Gherardin NA, Harrison SJ, et al. Spontaneous onset and transplant models of the Vk*MYC mouse show immunological sequelae comparable to human multiple myeloma. 2016, J Transl Med, 14, p259-268.



Faculty Research Themes

Cancer, Infection and Immunology

School Research Themes

Cancer in Medicine, Ageing



Research Opportunities

PhD, Masters by Research
Students who are interested in joining this project will need to consider their elegibility as well as other requirements before contacting the supervisor of this research

Graduate Research application

Honours application

Key Contact

For further information about this research, please contact a supervisor.

Department

Medicine and Radiology

Research Group / Unit / Centre

ACRF Translational Research Laboratory

Research Node

Royal Melbourne Hospital

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