Title:Targeting the Tumor Microenvironment by Intervention in Interleukin-1 Biology
Volume: 23
Issue: 32
Author(s): Elena Voronov and Ron N. Apte *
Affiliation:
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, 84105,Israel
Keywords:
IL-1, inflammation, immune response, malignant process, cytokine, antagonist.
Abstract: The importance of anti-tumor immunity in the outcome of cancer is now unequivocally established and
recent achivements in the field have stimulated the development of new immunotherapeutical approaches. In
invasive tumors, widespread inflammation promotes invasiveness and concomitantly also inhibits anti-tumor
immune responses. We suggest that efficient tumor treatment should target both the malignant cells and the tumor
microenvironment. Interleukin-1 (IL-1) is a pro-inflammatory as well as an immunostimulatory cytokine that is
abundant in the tumor microenvironment. Manipulation of IL-1 can thus serve as an immunotherapeutical approach
to reduce inflammation/immunosuppression and thus enhance anti-tumor immunity. The two major IL-1
agonistic molecules are IL-1α and IL-1β, which bind to the same IL-1 signaling receptor and induce the same
array of biological activities. The IL-1 receptor antagonist (IL-Ra) is a physiological inhibitor of IL-1 that binds
to its receptor without transmition of activation signals and thus serves as a decoy target. We have demonstrated
that IL-1α and IL-1β are different in terms of the producing cells and their compartmentalization and the amount.
IL-1α is mainly expressed intracellularly, in the cytosol, in the nucleus or exposed on the cell membrane, however,
it is rarely secreted. IL-1β is active only as a secreted molecule that is mainly produced by activated myeloid
cells. We have shown different functions of IL-1α and IL-1β in the malignant process. Thus, in its membrane-
associated form, IL-1α is mainly immunostimulatory, while IL-1β that is secreted into the tumor microenvironment
is mainly pro-inflammatory and promotes tumorigenesis, tumor invasiveness and immunosuppression.
These distinct functions of the IL-1 agonistic molecules are mainly manifested in early stages of tumor development
and the patterns of their expression dictate the direction of the malignant process. Here, we suggest that IL-1
modulation can serve as an effective mean to tilt the balance between inflammation and immunity in tumor sites,
towards the latter. Different agents that neutralize IL-1, mainly the IL-Ra and specific antibodies, exist. They are
safe and FDA-approved. The IL-1Ra has been widely and successfully used in patients with Rheumatoid arthritis,
autoinflammatory diseases and various other diseases that have an inflammatory component. Here, we provide
the rationale and experimental evidence for the use of anti-IL-1 agents in cancer patients, following first line
therapy to debulk the major tumor's mass. The considerations and constraints of using anti-IL-1 treatments in
cancer are also discussed. We hope that this review will stimulate studies that will fasten the application of IL-1
neutralization at the bedside of cancer patients.
