Abstract
2-fluorofucose (2FF) inhibits protein and cellular fucosylation. Afucosylation of IgG antibodies enhances antibody-dependent cell-mediated cytotoxicity by modulating antibody affinity for FcγRIIIa, which can impact secondary T-cell activation. Immune responses toward most common solid tumors are dominated by a humoral immune response rather than the presence of tumor-infiltrating cytotoxic T cells. IgG antibodies directed against numerous tumor-associated proteins are found in the sera of both patients with breast cancer and transgenic mice bearing mammary cancer. We questioned whether 2FF would have antitumor activity in two genetically distinct transgenic models; TgMMTV-neu (luminal B) and C3(1)-Tag (basal) mammary cancer. 2FF treatment significantly improved overall survival. The TgMMTV-neu doubled survival time compared with controls [P < 0.0001; HR, 7.04; 95% confidence interval (CI), 3.31-15.0], and survival was significantly improved in C3(1)-Tag (P = 0.0013; HR, 3.36; 95% CI, 1.58-7.14). 2FF treated mice, not controls, developed delayed-type hypersensitivity and T-cell responses specific for syngeneic tumor lysates (P < 0.0001). Serum IgG from 2FF-treated mice enhanced tumor lysis more efficiently than control sera (P = 0.004). Administration of 2FF for prophylaxis, at two different doses, significantly delayed tumor onset in both TgMMTV-neu; 20 mmol/L (P = 0.0004; HR, 3.55; 95% CI, 1.60-7.88) and 50 mmol/L (P = 0.0002; HR: 3.89; 95% CI, 1.71-8.86) and C3(1)-Tag; 20 mmol/L (P = 0.0020; HR, 2.51; 95% CI, 1.22-5.18), and 50 mmol/L (P = 0.0012; HR, 3.36; 95% CI, 1.57-7.18). Mammary cancer was prevented in 33% of TgMMTV-neu and 26% of C3(1)-Tag. 2FF has potent antitumor effects in mammary cancer models. The agent shows preclinical efficacy for both cancer treatment and prevention.
Highlights
Patients with breast cancer have robust type II tumor-directed immune responses with little evidence of type I immunity (1, 2)
Mice treated with 2FF doubled survival time to a median of 94 days after treatment was initiated, (HR, 7.04; 95% confidence interval (CI), 3.31–15.0)
Mice treated with 2FF survived a median of 43 days after treatment was initiated (HR, 3.36; 95% CI, 1.58–7.14)
Summary
Patients with breast cancer have robust type II tumor-directed immune responses with little evidence of type I immunity (1, 2). The dominance of a type II immune microenvironment is established early in breast tumorigenesis (3). Breast cancer is associated with abundant autoantibodies directed against tumorassociated antigens, high levels of tumor-infiltrating B cells, and few infiltrating CD8þ T cells in the majority of patients (2, 4, 5). Clinical studies of immune checkpoint inhibitor mAbs have shown that strategies which augment endogenous T-cell immunity can have an impact on tumor growth and overall survival in a variety of cancers where tumor-infiltrating T cells predominate (6). Agents designed to “unleash” the numerous tumor-specific endogenous antibodies and improve their antitumor activity could have a similar clinical impact in malignancies dominated by a humoral antibody response, such as breast cancer.
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