Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Cell Rep. 2023 Apr 25;42(4):112364. doi: 10.1016/j.celrep.2023.112364. Epub 2023 Apr 10.
The clinical response to immune checkpoint blockade (ICB) correlates with tumor-infiltrating cytolytic T lymphocytes (CTLs) prior to treatment. However, many of these inflamed tumors resist ICB through unknown mechanisms. We show that tumors with transcription elongation deficiencies (TE), which we previously reported as being resistant to ICB in mouse models and the clinic, have high baseline CTLs. We show that high baseline CTLs in TE tumors result from aberrant activation of the nucleic acid sensing-TBK1-CCL5/CXCL9 signaling cascade, which results in an immunosuppressive microenvironment with elevated regulatory T cells and exhausted CTLs. ICB therapy of TE tumors fail to increase CTL infiltration and suppress tumor growth in both experimental and clinical settings, suggesting that TE, along with surrogate markers of tumor immunogenicity such as tumor mutational burden and CTLs, should be considered in the decision process for patient immunotherapy indication.
免疫检查点阻断（ICB）的临床反应与治疗前肿瘤浸润的细胞毒性 T 淋巴细胞（CTL）相关。然而，许多这些炎症肿瘤通过未知的机制抵抗 ICB。我们表明，转录延伸缺陷（TE）的肿瘤，我们之前在小鼠模型和临床中报道为对 ICB 有抗性，具有高基线 CTL。我们表明，TE 肿瘤中的高基线 CTL 源自异常激活核酸感应-TBK1-CCL5/CXCL9 信号级联，导致具有升高的调节性 T 细胞和耗竭 CTL 的免疫抑制微环境。在实验和临床环境中，TE 肿瘤的 ICB 治疗未能增加 CTL 浸润并抑制肿瘤生长，这表明 TE 以及肿瘤免疫原性的替代标志物，如肿瘤突变负担和 CTL，应在患者免疫治疗指征的决策过程中考虑。
