Dendritic cells pulsed with penetratin-OLFM4 inhibit the growth and metastasis of melanoma in mice

Abstract

Cancer stem cells (CSCs) can self-renew and differentiate, contributing to tumor heterogeneity, metastasis, and recurrence. Their resistance to therapies, including immunotherapy, underscores the importance of targeting them for complete remission and relapse prevention. Olfactomedin 4 (OLFM4), a marker associated with various cancers such as colorectal cancer, is expressed on CSCs promoting immune evasion and tumorigenesis. However, its potential as a target for CSC-specific immunotherapy remains underexplored. The primary aim of this study is to evaluate the effectiveness of targeting OLFM4 with dendritic cell (DC)-based vaccines in inhibiting tumor growth and metastasis. To improve antigen delivery and immune response, OLFM4 was conjugated with a protein-transduction domain (PTD) from the antennapedia of Drosophila called penetratin, creating a fusion protein (P-OLFM4). The efficacy of DCs pulsed with P-OLFM4 (DCs [P-OLFM4]) was compared to DCs pulsed with OLFM4 (DCs [OLFM4]) and PBS (DCs [PBS]). DCs [P-OLFM4] inhibited tumor growth by 91.2 % and significantly reduced lung metastasis of OLFM4+ melanoma cells by 97 %, compared to the DCs [PBS]. DCs [OLFM4] also demonstrated a reduction in lung metastasis by 59.7 % compared to DCs [PBS]. Immunization with DCs [P-OLFM4] enhanced OLFM4-specific T-cell proliferation, interferon-γ production, and cytotoxic T cell activity in mice. The results indicate that OLFM4 is a viable target for CSC-focused immunotherapy. DC [P-OLFM4] vaccines can elicit robust immune responses, significantly inhibiting tumor growth and metastasis. This strategy holds promise for developing more effective cancer treatments that specifically target CSCs, potentially leading to better patient outcomes by reducing the likelihood of tumor relapse and metastasis.

Keywords: Cancer stem cells; Dendritic cells; Immunotherapy; Metastasis; Olfactomedin 4 (OLFM4).