The role of type I interferon in chronic lymphocytic leukemia

Type I interferon (IFN) has pleotropic and context-dependent biological effects. IFN's involvement in viral infections is well known but its precise role in cancer remains elusive. The aims of this thesis were to study the role of IFN in chronic lymphocytic leukemia (CLL), the most common adult leukemia. CLL cells were found to exhibit the capacity to both produce and respond to autocrine IFN. Leukemic cells from patients with clinically aggressive disease expressed higher IFN receptor levels and heightened responsiveness to IFN. Enhanced IFN sensitivity was associated with chemoresistance to CLL therapies including bruton’s tyrosine kinase inhibitors such as ibrutinib and Bcl-2 inhibitors such as venetoclax. The final section of this thesis described the results of a phase I clinical trial of the recombinant interleukin-1 (IL-1) receptor antagonist anakinra in CLL patients. Anakinra was found to upregulate IFN-signaling, decrease oxidative stress, and reduce nuclear factor kappa light chain enhancer of activated B cells (NFκB) signaling within CLL cells in vivo and in vitro. Increased IFN-signaling was associated with loss of an initial clinical response to anakinra. The results from this trial suggested anakinra acts as an NFκB inhibitor and may be a promising therapeutic candidate for CLL if the compensatory IFN response is simultaneously blocked. Collectively, the findings in this thesis have uncovered a pro-tumor effect of autocrine and paracrine IFN within CLL cells. Moreover, the observations illustrate a nuanced equilibrium between NFκB activation and IFN responses in the cancer context, mirroring phenomena described in infectious disease models. The results suggest that IFN blockade might be a viable strategy to enhance the therapeutic efficacy of existing CLL treatments in a subset of patients with aggressive disease.

Department dc:contributor.department

Immunology

Year dc:date.issued

2024

Author dc:creator

• LUO, YU XUAN

Advisor dc:contributor.advisor

• Spaner, David E

• Chronic lymphocytic leukemia
• NF-keppa-B
• Type I Inteferon

Statement dc:rights

• Attribution-NoDerivatives 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nd/4.0/

Handle dc:identifier.uri

http://hdl.handle.net/1807/139639

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/139639