SITC 2024: Wnt Inhibitor Emerges as Regulator of Breast Cancer Progression

By: Julia Cipriano, MS
Posted: Tuesday, November 12, 2024

According to Seunghyun Lee, PhD, of Washington University School of Medicine, St. Louis, and colleagues, cancer-associated fibroblast–derived Dickkopf-1 (DDK1) seems to impair antitumor immunity in breast cancer via the suppression of natural killer cell–mediated cytotoxicity. Their preclinical findings, which were presented during the 2024 Society for Immunotherapy of Cancer (SITC) Annual Meeting (Abstract 978), identified the Wnt inhibitor as a regulator of disease progression.

Mice harboring breast cancer demonstrated elevated serum levels of DKK1; neutralizing this protein appeared to significantly reduce primary tumor growth and metastatic dissemination. Treatment with an anti-DKK1 antibody also seemed to significantly increase the efficacy of chemotherapy plus anti–PD-1 antibodies. Expression of DKK1 was seen at the tumor site in cancer-associated fibroblasts but not in the cancer cells or immune populations. In cancer-associated fibroblasts, deletion of DKK1 appeared to result in significantly reduced primary tumor growth while maintaining comparable serum DKK1 levels; the investigators thus noted that locally produced DKK1 supported tumor growth.

RNA sequencing of tumors treated with an anti-DKK1 antibody did not show changes related to cell viability or proliferation; however, the investigators reported upregulation of genes related to immune response. Confirming these findings, treatment with an anti-DKK1 antibody was not found to reduce tumor growth in immunocompromised NOD/SCID/IL2Rg-null (NSG) mice. Only natural killer cell depletion negated the antitumor effects of the anti-DKK1 antibody, according to the investigators. In vitro assays further demonstrated the capacity of DKK1 for reducing perforin levels and natural killer cell cytotoxicity against human and murine tumor cells.  

When the investigators turned to clinical findings, patients with progressive bone metastatic vs stable breast cancer had significantly elevated levels of DKK1, and natural killer cells from those with progressive disease had reduced perforin and granzyme B expression at follow-up visits than at baseline. These observations seemed to indicate reduced cytotoxicity.

Disclosure: No information regarding conflicts of interest was provided.

2024 SITC Annual Meeting

---