Burga Rachel A, Thorn Mitchell, Point Gary R, Guha Prajna, Nguyen Cang T, Licata Lauren A, DeMatteo Ronald P, Ayala Alfred, Joseph Espat N, Junghans Richard P, Katz Steven C
Division of Surgical Oncology, Department of Surgery, Roger Williams Medical Center, 825 Chalkstone Avenue, Prior 4, Providence, RI, 02908, USA.
Cancer Immunol Immunother. 2015 Jul;64(7):817-29. doi: 10.1007/s00262-015-1692-6. Epub 2015 Apr 8.
Chimeric antigen receptor-modified T cell (CAR-T) technology, a promising immunotherapeutic tool, has not been applied specifically to treat liver metastases (LM). While CAR-T delivery to LM can be optimized by regional intrahepatic infusion, we propose that liver CD11b+Gr-1+ myeloid-derived suppressor cells (L-MDSC) will inhibit the efficacy of CAR-T in the intrahepatic space. We studied anti-CEA CAR-T in a murine model of CEA+ LM and identified mechanisms through which L-MDSC expand and inhibit CAR-T function. We established CEA+ LM in mice and studied purified L-MDSC and responses to treatment with intrahepatic anti-CEA CAR-T infusions. L-MDSC expanded threefold in response to LM, and their expansion was dependent on GM-CSF, which was produced by tumor cells. L-MDSC utilized PD-L1 to suppress anti-tumor responses through engagement of PD-1 on CAR-T. GM-CSF, in cooperation with STAT3, promoted L-MDSC PD-L1 expression. CAR-T efficacy was rescued when mice received CAR-T in combination with MDSC depletion, GM-CSF neutralization to prevent MDSC expansion, or PD-L1 blockade. As L-MDSC suppressed anti-CEA CAR-T, infusion of anti-CEA CAR-T in tandem with agents targeting L-MDSC is a rational strategy for future clinical trials.
嵌合抗原受体修饰的T细胞（CAR-T）技术是一种很有前景的免疫治疗工具，但尚未专门应用于治疗肝转移瘤（LM）。虽然通过肝内区域输注可以优化CAR-T向LM的递送，但我们认为肝脏CD11b+Gr-1+髓源性抑制细胞（L-MDSC）会抑制肝内空间中CAR-T的疗效。我们在CEA+肝转移瘤的小鼠模型中研究了抗CEA CAR-T，并确定了L-MDSC扩增并抑制CAR-T功能的机制。我们在小鼠中建立了CEA+肝转移瘤，并研究了纯化的L-MDSC以及肝内抗CEA CAR-T输注治疗后的反应。L-MDSC对肝转移瘤的反应扩增了三倍，其扩增依赖于肿瘤细胞产生的粒细胞-巨噬细胞集落刺激因子（GM-CSF）。L-MDSC利用程序性死亡配体1（PD-L1）通过与CAR-T上的程序性死亡受体1（PD-1）结合来抑制抗肿瘤反应。GM-CSF与信号转导和转录激活因子3（STAT3）协同促进L-MDSC的PD-L1表达。当小鼠接受CAR-T联合MDSC清除、GM-CSF中和以防止MDSC扩增或PD-L1阻断时，CAR-T的疗效得以恢复。由于L-MDSC抑制抗CEA CAR-T，因此将抗CEA CAR-T与靶向L-MDSC的药物串联输注是未来临床试验的合理策略。
