Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, California.
Department of Developmental and Cell Biology, University of California, Irvine, California.
Cancer Immunol Res. 2022 May 3;10(5):612-625. doi: 10.1158/2326-6066.CIR-21-0690.
Immune-checkpoint inhibitors have had impressive efficacy in some patients with cancer, reinvigorating long-term durable immune responses against tumors. Despite the clinical success of these therapies, most patients with cancer continue to be unresponsive to these treatments, highlighting the need for novel therapeutic options. Although P-selectin glycoprotein ligand-1 (PSGL-1) has been shown to inhibit immune responses in a variety of disease models, previous work has yet to address whether PSGL-1 can be targeted therapeutically to promote antitumor immunity. Using an aggressive melanoma tumor model, we targeted PSGL-1 in tumor-bearing mice and found increased effector CD4+ and CD8+ T-cell responses and decreased regulatory T cells (Treg) in tumors. T cells exhibited increased effector function, activation, and proliferation, which delayed tumor growth in mice after anti-PSGL-1 treatment. Targeting PD-1 in PSGL-1-deficient, tumor-bearing mice led to an increased frequency of mice with complete tumor eradication. Targeting both PSGL-1 and PD-1 in wild-type tumor-bearing mice also showed enhanced antitumor immunity and slowed melanoma tumor growth. Our findings showed that therapeutically targeting the PSGL-1 immune checkpoint can reinvigorate antitumor immunity and suggest that targeting PSGL-1 may represent a new therapeutic strategy for cancer treatment.
免疫检查点抑制剂在一些癌症患者中具有显著的疗效，重新激发了针对肿瘤的长期持久免疫反应。尽管这些疗法在临床上取得了成功，但大多数癌症患者仍然对这些治疗无反应，这凸显了需要新的治疗选择。尽管 P 选择素糖蛋白配体-1（PSGL-1）已被证明可抑制多种疾病模型中的免疫反应，但以前的工作尚未解决 PSGL-1 是否可以作为治疗靶点来促进抗肿瘤免疫。我们在荷瘤小鼠中靶向 PSGL-1 使用侵袭性黑色素瘤肿瘤模型，发现肿瘤中效应性 CD4+和 CD8+T 细胞反应增加，调节性 T 细胞（Treg）减少。T 细胞表现出增强的效应功能、激活和增殖，这在抗 PSGL-1 治疗后延迟了小鼠的肿瘤生长。在 PSGL-1 缺陷型荷瘤小鼠中靶向 PD-1 导致更多的小鼠完全消除肿瘤。在野生型荷瘤小鼠中靶向 PSGL-1 和 PD-1 也显示出增强的抗肿瘤免疫并减缓黑色素瘤肿瘤生长。我们的研究结果表明，靶向 PSGL-1 免疫检查点的治疗可以重新激发抗肿瘤免疫，并表明靶向 PSGL-1 可能代表癌症治疗的一种新的治疗策略。
