Department of Biological Sciences, Clemson University, Clemson, South Carolina, United States of America.
Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America.
PLoS One. 2021 Jun 2;16(6):e0252662. doi: 10.1371/journal.pone.0252662. eCollection 2021.
Breast cancer cells were reported to up-regulate human prolactin receptor (PRLR) to assist their growth through the utilization of prolactin (PRL) as the growth factor, which makes PRLR a potential therapeutic target for breast cancer. On the other hand, advanced cancer cells tend to down-regulate or shed off stress signal proteins to evade immune surveillance and elimination. In this report, we created a fusion protein consisting of the extracellular domain of MHC class I chain-related protein (MICA), a stress signal protein and ligand of the activating receptor NKG2D of natural killer (NK) cells, and G129R, an antagonistic variant of PRL. We hypothesize that the MICA portion of the fusion protein binds to NKG2D to activate NK cells and the G129R portion binds to PRLR on breast cancer cells, so that the activated NK cells will kill the PRLR-positive breast cancer cells. We demonstrated that the MICA-G129R fusion protein not only binds to human natural killer NK-92 cells and PRLR-positive human breast cancer T-47D cells, but also promotes NK cells to release granzyme B and IFN-γ and enhances the cytotoxicity of NK cells specifically on PRLR-positive cells. The fusion protein, therefore, represents a new approach for the development of breast cancer specific immunotherapy.
据报道，乳腺癌细胞上调人泌乳素受体（PRLR），通过利用泌乳素（PRL）作为生长因子来辅助其生长，这使得 PRLR 成为乳腺癌潜在的治疗靶点。另一方面，晚期癌细胞往往会下调或脱落应激信号蛋白，以逃避免疫监视和消除。在本报告中，我们构建了一种融合蛋白，由 MHC Ⅰ类链相关蛋白（MICA）的细胞外结构域、应激信号蛋白和自然杀伤（NK）细胞激活受体 NKG2D 的配体组成，以及 PRL 的拮抗变体 G129R。我们假设融合蛋白的 MICA 部分与 NKG2D 结合以激活 NK 细胞，而 G129R 部分与乳腺癌细胞上的 PRLR 结合，从而使激活的 NK 细胞杀死 PRLR 阳性乳腺癌细胞。我们证明了 MICA-G129R 融合蛋白不仅与人类自然杀伤 NK-92 细胞和 PRLR 阳性人乳腺癌 T-47D 细胞结合，还促进 NK 细胞释放颗粒酶 B 和 IFN-γ，并增强 NK 细胞对 PRLR 阳性细胞的细胞毒性。因此，该融合蛋白代表了开发乳腺癌特异性免疫疗法的新方法。
