Mechanism of inert inflammation in an immune checkpoint blockade-resistant tumor subtype bearing transcription elongation defects

• DOI: 10.1016/j.celrep.2023.112364
• Publication Date: 2023-04-10T22:50:03Z
• Authors: Vishnu Modur; Belal Muhammad; Jun-Qi Yang; Yi Zheng; Kakajan Komurov; Fukun Guo
• Keywords: Inflammation; 0303 health sciences; QH301-705.5; 3. Good health; Mice; 03 medical and health sciences; Neoplasms; Tumor Microenvironment; Animals; Humans; Immunotherapy; Biology (General); CP: Cancer; Immune Checkpoint Inhibitors; Signal Transduction

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 (TEdef+), 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 TEdef+ 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 TEdef+ tumors fail to increase CTL infiltration and suppress tumor growth in both experimental and clinical settings, suggesting that TEdef+, 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.