Department of Hepatobiliary Hernia Surgery, Hexian Memorial Affiliated Hospital of Southern Medical University, Guangzhou, 511400, China.
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
J Mol Histol. 2024 Oct;55(5):785-792. doi: 10.1007/s10735-024-10230-4. Epub 2024 Aug 3.
Immune checkpoint blockade therapy has demonstrated significant therapeutic effects in certain types of cancers. However, there is limited reporting on the influence of physical activity on its efficacy. This study aimed to investigate the impact of physical activity on anti-PDL-1-mediated immune checkpoint therapy and the interplay of immune cells therein. HePa1-6 tumor-bearing mice were treated with anti-PDL-1 in conjunction with physical activity to assess tumor progression. Flow cytometry was utilized to analyze immune cell infiltration and differentiation levels within the tumor. The expression of HIF-a/CEACAM1 within the tumor due to physical activity was evaluated. HePa1-6 cells with high CEACAM1 expression were validated in mice to determine their inhibitory effects on immune cell proliferation and differentiation. A CD3/CEACAM1 chimeric antibody was developed for treating CEACAM1-overexpressing tumors, and flow cytometry was employed to assess T-cell response. Physical activity enhanced the efficacy of anti-PDL1 by suppressing the HIF-a/CEACAM1 axis within the tumor. In vivo experiments revealed that tumors with high CEACAM1 expression decreased infiltration and activation of CD8 + T cells within the tumor, suppressing T cell cytotoxicity without affecting Treg infiltration. In vitro, high CEACAM1 expression impacted the proliferation and activation of CD8 + T cells in a co-culture system. The constructed CD3/CEACAM1 chimeric antibody significantly activated the TCR within CEACAM1-overexpressing tumors and inhibited tumor progression. The findings suggest that physical activity augments the effectiveness of immune checkpoint blockade by inhibiting the intratumoral HIF1-α/CEACM1 axis.
免疫检查点阻断疗法在某些类型的癌症中显示出显著的治疗效果。然而，关于体力活动对其疗效的影响的报道有限。本研究旨在探讨体力活动对抗 PD-1 介导的免疫检查点治疗的影响及其对免疫细胞的相互作用。用抗 PD-1 联合体力活动治疗荷瘤 HePa1-6 小鼠，评估肿瘤进展。利用流式细胞术分析肿瘤内免疫细胞浸润和分化水平。评估由于体力活动导致肿瘤内 HIF-a/CEACAM1 的表达。在小鼠中验证具有高 CEACAM1 表达的 HePa1-6 细胞，以确定它们对免疫细胞增殖和分化的抑制作用。开发了一种 CD3/CEACAM1 嵌合抗体用于治疗 CEACAM1 过表达的肿瘤，并利用流式细胞术评估 T 细胞反应。体力活动通过抑制肿瘤内的 HIF-a/CEACAM1 轴增强了抗 PD-1 的疗效。体内实验表明，高 CEACAM1 表达的肿瘤减少了肿瘤内 CD8+T 细胞的浸润和激活，抑制了 T 细胞的细胞毒性而不影响 Treg 的浸润。在体外，高 CEACAM1 表达影响共培养系统中 CD8+T 细胞的增殖和激活。构建的 CD3/CEACAM1 嵌合抗体显著激活了 CEACAM1 过表达肿瘤内的 TCR，并抑制了肿瘤进展。研究结果表明，体力活动通过抑制肿瘤内的 HIF1-α/CEACM1 轴增强了免疫检查点阻断的效果。
