טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKan Tal
SubjectThe Immunological Effects Underlining the Anti-Tumorigenic
Properties of the Pro-Inflammatory Cytokine
IL-31
DepartmentDepartment of Medicine
Supervisors PROF. Yuval Shaked
PROF. Ami Aronheim


Abstract

Recent advances in cancer immunotherapy have added a fourth pillar to the treatments for cancer in addition to surgery, chemotherapy, and radiation therapy. Still, many patients do not benefit from these therapies due to a lack of response, acquired resistance, adverse effects, etc. Therefore, there is still a great need for novel immunomodulatory agents that are able to induce antitumor immunity as a treatment of cancer. We have previously shown that IL - 31, a cytokine from the IL - 6 family, acts as an antiangiogenic agent. However, IL-31 has a role in inflammation and in the regulation of different immune cell populations which was not explored in cancer. Here, we characterized the antitumorigenic immunomodulatory effects of IL - 31 in a breast cancer context.  In an in vivo murine breast carcinoma model, we demonstrated that the growth rate of IL-31-overexpressing tumors is decreased due to an antitumor immunological response induced both systemically and locally in the tumor. Specifically, CD8 cytotoxic T cell activity is increased, whereas the levels of CD4? T cells, myeloid derived suppressor cells (MDSCs), and tumor associated macrophages were decreased in IL-31-expressing tumors. These cellular changes were accompanied by a molecular profile associated with an antitumor immune response. We showed in the tumor that the levels of the immunosuppressive cytokine IL-10 decreased, while the levels of the T cell growth factor IL-2 increased. Moreover, we found elevated levels of granzyme B, a molecule secreted by CD8 cytotoxic T cells to induce apoptosis in cancer cells. In vitro, IL-31 directly inhibited CD4 T cell proliferation and the expression of Th2 drives GATA3 and IL-4 only in uncommitted cells. IL-31 also increased CD8 T cell activation indirectly via MDSCs, and decreased MDSC motility. Clinically, consistent with the mouse data, alterations in immune cell composition in breast cancer biopsies were found to correlate with high expression of IL-31Ra in breast cancer patients. Moreover, we found that high co-expression of IL-31Ra, IL-2 and IL-4 in tumors correlates with increased survival. Lastly, as the data we have generated suggests that IL-31 may have clinical relevance and it may improve prognosis, we aimed to further study its therapeutic potential in breast cancer. We cloned a recombinant murine IL-31 molecule fused to an IgG heavy chain via a linker region. This allowed to increase the stability and half-life of IL-31 in circulation while retaining its biological activity. Injections of IL-31 fused to IgG to breast tumors bearing mice exhibited antitumor activity when compared to controls. Collectively, our findings demonstrate that IL-31 induces antitumor immunity, highlighting its potential to be used as a therapeutic immunomodulatory agent.