Mechanism of inert inflammation in an immune checkpoint blockade-resistant tumor subtype bearing transcription elongation defects
Summary: 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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723003753 |
| _version_ | 1797848282162003968 |
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| author | Vishnu Modur Belal Muhammad Jun-Qi Yang Yi Zheng Kakajan Komurov Fukun Guo |
| author_facet | Vishnu Modur Belal Muhammad Jun-Qi Yang Yi Zheng Kakajan Komurov Fukun Guo |
| author_sort | Vishnu Modur |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-04-09T18:25:01Z |
| format | Article |
| id | doaj.art-fda98c52b17248c99d73d17a3352df8d |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-09T18:25:01Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-fda98c52b17248c99d73d17a3352df8d2023-04-12T04:11:43ZengElsevierCell Reports2211-12472023-04-01424112364Mechanism of inert inflammation in an immune checkpoint blockade-resistant tumor subtype bearing transcription elongation defectsVishnu Modur0Belal Muhammad1Jun-Qi Yang2Yi Zheng3Kakajan Komurov4Fukun Guo5Division of Experimental Hematology and Cancer Biology, Children’s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Corresponding authorDivision of Experimental Hematology and Cancer Biology, Children’s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USADivision of Experimental Hematology and Cancer Biology, Children’s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USADivision of Experimental Hematology and Cancer Biology, Children’s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Corresponding authorChampions Oncology, Inc, Hackensack, NJ, USA; Corresponding authorDivision of Experimental Hematology and Cancer Biology, Children’s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723003753CP: Cancer |
| spellingShingle | Vishnu Modur Belal Muhammad Jun-Qi Yang Yi Zheng Kakajan Komurov Fukun Guo Mechanism of inert inflammation in an immune checkpoint blockade-resistant tumor subtype bearing transcription elongation defects Cell Reports CP: Cancer |
| title | Mechanism of inert inflammation in an immune checkpoint blockade-resistant tumor subtype bearing transcription elongation defects |
| title_full | Mechanism of inert inflammation in an immune checkpoint blockade-resistant tumor subtype bearing transcription elongation defects |
| title_fullStr | Mechanism of inert inflammation in an immune checkpoint blockade-resistant tumor subtype bearing transcription elongation defects |
| title_full_unstemmed | Mechanism of inert inflammation in an immune checkpoint blockade-resistant tumor subtype bearing transcription elongation defects |
| title_short | Mechanism of inert inflammation in an immune checkpoint blockade-resistant tumor subtype bearing transcription elongation defects |
| title_sort | mechanism of inert inflammation in an immune checkpoint blockade resistant tumor subtype bearing transcription elongation defects |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723003753 |
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