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.
摘要：
肿瘤干细胞(CSCs)可以自我更新和分化,导致肿瘤异质性，转移,和复发。他们对治疗的抵制，包括免疫疗法,强调了以完全缓解和预防复发为目标的重要性。Olfactomedin4(OLFM4),与各种癌症相关的标记物，如结直肠癌，在促进免疫逃避和肿瘤发生的CSC上表达。然而,其作为CSC特异性免疫治疗靶标的潜力仍未得到充分开发.这项研究的主要目的是评估用基于树突状细胞（DC）的疫苗靶向OLFM4抑制肿瘤生长和转移的有效性。为了改善抗原递送和免疫反应，OLFM4与来自果蝇触角的蛋白质转导域（PTD）缀合，称为penetratin，产生融合蛋白(P-OLFM4)。将用P-OLFM4(DC[P-OLFM4])脉冲的DC的功效与用OLFM4(DC[OLFM4])和PBS(DC[PBS])脉冲的DC的功效进行比较。DCs[P-OLFM4]抑制肿瘤生长达91.2%,显著降低OLFM4+黑色素瘤细胞的肺转移达97%,与DC[PBS]相比。与DC[PBS]相比,DC[OLFM4]还显示肺转移减少59.7%。用DC[P-OLFM4]免疫增强OLFM4特异性T细胞增殖,干扰素-γ生产，和小鼠的细胞毒性T细胞活性。结果表明OLFM4是CSC聚焦免疫疗法的可行靶标。DC[P-OLFM4]疫苗可以引发强烈的免疫反应，显著抑制肿瘤生长和转移。这种策略有望开发更有效的癌症治疗方法，专门针对CSC。通过降低肿瘤复发和转移的可能性可能导致更好的患者预后。
