STING signalling compensates for low tumour mutation burden to drive anti-tumour immunityResearch in context
Summary: Background: While mutation-derived neoantigens are well recognized in generating anti-tumour T cell response, increasing evidences highlight the complex association between tumour mutation burden (TMB) and tumour infiltrating lymphocytes (TILs). The exploration of non-TMB determinants of a...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396424000707 |
| _version_ | 1827341716199309312 |
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| author | Jiayi Tan Colt A. Egelston Weihua Guo Jeremy M. Stark Peter P. Lee |
| author_facet | Jiayi Tan Colt A. Egelston Weihua Guo Jeremy M. Stark Peter P. Lee |
| author_sort | Jiayi Tan |
| collection | DOAJ |
| description | Summary: Background: While mutation-derived neoantigens are well recognized in generating anti-tumour T cell response, increasing evidences highlight the complex association between tumour mutation burden (TMB) and tumour infiltrating lymphocytes (TILs). The exploration of non-TMB determinants of active immune response could improve the prognosis prediction and provide guidance for current immunotherapy. Methods: The transcriptomic and whole exome sequence data in The Cancer Genome Atlas were used to examine the relationship between TMB and exhausted CD8+ T cells (Tex), as an indicator of tumour antigen-specific T cells across nine major cancer types. Computational clustering analysis was performed on 4510 tumours to identify different immune profiles. NanoString gene expression analysis and single cell RNA-seq analysis using fresh human breast cancer were performed for finding validation. Findings: TMB was found to be poorly correlated with active immune response in various cancer types. Patient clustering analysis revealed a group of tumours with abundant Tex but low TMB. In those tumours, we observed significantly higher expression of the stimulator of interferon genes (STING) signalling. Dendritic cells, particularly those of BATF3+ lineage, were also found to be essential for accumulation of Tex within tumours. Mechanistically, loss of genomic and cellular integrity, marked by decreased DNA damage repair, defective replication stress response, and increased apoptosis were shown to drive STING activation. Interpretation: These results highlight that TMB alone does not fully predict tumour immune profiles, with STING signalling compensating for low TMB in non-hypermutated tumours to enhance anti-tumour immunity. Translating these results, STING agonists may benefit patients with non-hypermutated tumours. STING activation may serve as an additional biomarker to predict response to immune checkpoint blockades alongside TMB. Our research also unravelled the interplay between genomic instability and STING activation, informing potential combined chemotherapy targeting the axis of genomic integrity and immunotherapy. Funding: City of Hope Christopher Family Endowed Innovation Fund for Alzheimer’s Disease and Breast Cancer Research in honor of Vineta Christopher; Breast Cancer Alliance Early Career Investigator Award; National Cancer Institute of the National Institutes of Health under award number R01CA256989 and R01CA240392. |
| first_indexed | 2024-03-07T21:53:03Z |
| format | Article |
| id | doaj.art-29ea860f8665407ebbf235dc09528463 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-07T21:53:03Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-29ea860f8665407ebbf235dc095284632024-02-25T04:35:53ZengElsevierEBioMedicine2352-39642024-03-01101105035STING signalling compensates for low tumour mutation burden to drive anti-tumour immunityResearch in contextJiayi Tan0Colt A. Egelston1Weihua Guo2Jeremy M. Stark3Peter P. Lee4Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA; Irell & Manella Graduate School of Biological Sciences, City of Hope Comprehensive Cancer Center, Duarte, CA, USADepartment of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USADepartment of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USADepartment of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA, USADepartment of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA; Corresponding author.Summary: Background: While mutation-derived neoantigens are well recognized in generating anti-tumour T cell response, increasing evidences highlight the complex association between tumour mutation burden (TMB) and tumour infiltrating lymphocytes (TILs). The exploration of non-TMB determinants of active immune response could improve the prognosis prediction and provide guidance for current immunotherapy. Methods: The transcriptomic and whole exome sequence data in The Cancer Genome Atlas were used to examine the relationship between TMB and exhausted CD8+ T cells (Tex), as an indicator of tumour antigen-specific T cells across nine major cancer types. Computational clustering analysis was performed on 4510 tumours to identify different immune profiles. NanoString gene expression analysis and single cell RNA-seq analysis using fresh human breast cancer were performed for finding validation. Findings: TMB was found to be poorly correlated with active immune response in various cancer types. Patient clustering analysis revealed a group of tumours with abundant Tex but low TMB. In those tumours, we observed significantly higher expression of the stimulator of interferon genes (STING) signalling. Dendritic cells, particularly those of BATF3+ lineage, were also found to be essential for accumulation of Tex within tumours. Mechanistically, loss of genomic and cellular integrity, marked by decreased DNA damage repair, defective replication stress response, and increased apoptosis were shown to drive STING activation. Interpretation: These results highlight that TMB alone does not fully predict tumour immune profiles, with STING signalling compensating for low TMB in non-hypermutated tumours to enhance anti-tumour immunity. Translating these results, STING agonists may benefit patients with non-hypermutated tumours. STING activation may serve as an additional biomarker to predict response to immune checkpoint blockades alongside TMB. Our research also unravelled the interplay between genomic instability and STING activation, informing potential combined chemotherapy targeting the axis of genomic integrity and immunotherapy. Funding: City of Hope Christopher Family Endowed Innovation Fund for Alzheimer’s Disease and Breast Cancer Research in honor of Vineta Christopher; Breast Cancer Alliance Early Career Investigator Award; National Cancer Institute of the National Institutes of Health under award number R01CA256989 and R01CA240392.http://www.sciencedirect.com/science/article/pii/S2352396424000707Tumour mutation burdenExhausted T cellsSTINGTumour microenvironment |
| spellingShingle | Jiayi Tan Colt A. Egelston Weihua Guo Jeremy M. Stark Peter P. Lee STING signalling compensates for low tumour mutation burden to drive anti-tumour immunityResearch in context EBioMedicine Tumour mutation burden Exhausted T cells STING Tumour microenvironment |
| title | STING signalling compensates for low tumour mutation burden to drive anti-tumour immunityResearch in context |
| title_full | STING signalling compensates for low tumour mutation burden to drive anti-tumour immunityResearch in context |
| title_fullStr | STING signalling compensates for low tumour mutation burden to drive anti-tumour immunityResearch in context |
| title_full_unstemmed | STING signalling compensates for low tumour mutation burden to drive anti-tumour immunityResearch in context |
| title_short | STING signalling compensates for low tumour mutation burden to drive anti-tumour immunityResearch in context |
| title_sort | sting signalling compensates for low tumour mutation burden to drive anti tumour immunityresearch in context |
| topic | Tumour mutation burden Exhausted T cells STING Tumour microenvironment |
| url | http://www.sciencedirect.com/science/article/pii/S2352396424000707 |
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