Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade [RNA-Seq]. Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade [RNA-Seq]

CAR-T cell therapy is effective in hematologic malignancies but not in solid tumors. In breast and lung cancer patients, CAR-T cells targeting ROR1 infiltrated tumors poorly and became dysfunctional. To test strategies for enhancing efficacy, we induced ROR1+ lung tumors in KrasLSL-G12D/+;p53fl/f mice. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently controlled tumor growth but infiltrated tumors poorly and lost function, as observed in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activated tumor macrophages to express T cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improved CAR-T mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic. Overall design: 9 samples of bulk RNA sequencing from murine lung tumors treated in vivo +/- chemotherapy

CAR-T细胞治疗（CAR-T cell therapy）对血液系统恶性肿瘤具有明确疗效，但在实体瘤中效果不佳。在乳腺癌及肺癌患者体内，靶向ROR1的CAR-T细胞肿瘤浸润能力薄弱且功能失调。为探究增强其疗效的策略，我们在KrasLSL-G12D/+;p53fl/f小鼠中诱导构建了ROR1阳性肺部肿瘤模型。经环磷酰胺（cyclophosphamide, Cy）进行淋巴清除后输注的小鼠ROR1 CAR-T细胞，可暂时抑制肿瘤生长，但肿瘤浸润能力不足且功能丧失，与临床患者中的观测结果一致。在该淋巴清除方案中加入奥沙利铂（oxaliplatin, Ox），可激活肿瘤巨噬细胞表达T细胞招募趋化因子，进而改善CAR-T细胞的肿瘤浸润情况、重塑肿瘤微环境，并提升肿瘤对抗PD-L1的敏感性。奥沙利铂/环磷酰胺联合抗PD-L1的联合治疗方案可协同增强CAR-T细胞介导的肿瘤控制效果并延长小鼠生存期，为临床中提升CAR-T细胞治疗疗效提供了可行思路。整体实验设计：取自经体内化疗/未化疗处理的小鼠肺部肿瘤的批量RNA测序样本，共9份。