Interferon + Resveratrol in Mutant p53 CLL

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Immunotherapeutic potential of interferon (IFN)-alpha and

resveratrol

Jelena Tomic, Dionne White, Liwei He, Yaacov Ben-,

Spaner. University of Toronto, Toronto, ON, Canada, Sunnybrook

Research Institute, Toronto, ON, Canada, Sanofi Pasteur, Toronto,

ON, Canada

The interferons (IFNs) are a group of proteins with potent

immunomodulatory properties and clinical activity in some cancers,

including B cell leukemias such as Chronic Lymphocytic Leukemia

(CLL). Unfortunately, patients with more aggressive disease are

usually resistant to treatment with IFN. Therefore, it is essential

to understand why IFNs do not work in advanced stage tumors in order

to improve effectiveness of IFN-based treatments.

IFN activates primarily the transcription factor STAT1 (a tumor

suppressor). A minor pathway of IFN-signalling is through STAT3 (an

oncogene). We have found that concomitant treatment with phorbol

esters (which are tumor promoters) enhances the minor pathway. As a

result of these studies, we speculated that deviation of IFN

signalling towards STAT3 is a tumor-promoting event. Therefore,

cancerous events associated with advanced stage cancer disease might

similarly affect IFN-signalling and be responsible for the

ineffectiveness of IFN as a single agent in advanced stage disease.

In particular, dysfunction of tumor suppressor p53 is a common event

in advanced stage tumors.

Our preliminary results with CLL B cells from patients who no longer

express p53 suggest that the loss of functional p53 plays a role in

deviating IFN-signalling in favour of STAT3. Accordingly, we

hypothesize that p53 dysfunction promotes tumor progression in part

by skewing IFN-signalling towards STAT3 and inhibiting the

immunogenic activity of IFN. The experiments to test this hypothesis

have been extended to B cells from p53+/+ and p53-/- mice, and human

B cell lines BL41 and BL41tsp53 (containing a temperature sensitive

p53 transgene which allows us to manipulate the activity of p53) as

well as TK6 and NH32 (a knockout derived from TK6) to represent

isogenic B cells that differ in their p53 status.

To date, it is still unclear how the loss of p53 promotes IFN-

signalling towards STAT3. However, our preliminary results show that

inhibition of IFN-mediated STAT3 activation by resveratrol (a

component found in red grapes) may have rendered leukemic cells more

susceptible to immunological clearance by T cells, both in vitro and

in vivo. These findings suggest the use of IFN+resveratrol in the

treatment of leukemias, and by extension many other cancers.