Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response
Abstract With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis o...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-05-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38271-5 |
| _version_ | 1797827422710661120 |
|---|---|
| author | Meghana Pagadala Timothy J. Sears Victoria H. Wu Eva Pérez-Guijarro Hyo Kim Andrea Castro James V. Talwar Cristian Gonzalez-Colin Steven Cao Benjamin J. Schmiedel Shervin Goudarzi Divya Kirani Jessica Au Tongwu Zhang Teresa Landi Rany M. Salem Gerald P. Morris Olivier Harismendy Sandip Pravin Patel Ludmil B. Alexandrov Jill P. Mesirov Maurizio Zanetti Chi-Ping Day Chun Chieh Fan Wesley K. Thompson Glenn Merlino J. Silvio Gutkind Pandurangan Vijayanand Hannah Carter |
| author_facet | Meghana Pagadala Timothy J. Sears Victoria H. Wu Eva Pérez-Guijarro Hyo Kim Andrea Castro James V. Talwar Cristian Gonzalez-Colin Steven Cao Benjamin J. Schmiedel Shervin Goudarzi Divya Kirani Jessica Au Tongwu Zhang Teresa Landi Rany M. Salem Gerald P. Morris Olivier Harismendy Sandip Pravin Patel Ludmil B. Alexandrov Jill P. Mesirov Maurizio Zanetti Chi-Ping Day Chun Chieh Fan Wesley K. Thompson Glenn Merlino J. Silvio Gutkind Pandurangan Vijayanand Hannah Carter |
| author_sort | Meghana Pagadala |
| collection | DOAJ |
| description | Abstract With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy. |
| first_indexed | 2024-04-09T12:48:03Z |
| format | Article |
| id | doaj.art-1886eb37a6cb4e559bd4787806656c26 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T12:48:03Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-1886eb37a6cb4e559bd4787806656c262023-05-14T11:20:48ZengNature PortfolioNature Communications2041-17232023-05-0114112210.1038/s41467-023-38271-5Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy responseMeghana Pagadala0Timothy J. Sears1Victoria H. Wu2Eva Pérez-Guijarro3Hyo Kim4Andrea Castro5James V. Talwar6Cristian Gonzalez-Colin7Steven Cao8Benjamin J. Schmiedel9Shervin Goudarzi10Divya Kirani11Jessica Au12Tongwu Zhang13Teresa Landi14Rany M. Salem15Gerald P. Morris16Olivier Harismendy17Sandip Pravin Patel18Ludmil B. Alexandrov19Jill P. Mesirov20Maurizio Zanetti21Chi-Ping Day22Chun Chieh Fan23Wesley K. Thompson24Glenn Merlino25J. Silvio Gutkind26Pandurangan Vijayanand27Hannah Carter28Biomedical Sciences Program, University of California San DiegoBioinformatics and Systems Biology Program, University of California San DiegoDepartment of Pharmacology, UCSD Moores Cancer CenterLaboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health (NIH)Undergraduate Bioengineering Program, Jacobs School of Engineering, University of California San DiegoBioinformatics and Systems Biology Program, University of California San DiegoBioinformatics and Systems Biology Program, University of California San DiegoLa Jolla Institute for ImmunologyDivision of Epidemiology, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San DiegoLa Jolla Institute for ImmunologyCanyon Crest AcademyUndergraduate Biology and Bioinformatics Program, University of California San DiegoBioinformatics and Systems Biology Program, University of California San DiegoDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH)Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH)Division of Epidemiology, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San DiegoDepartment of Pathology, University of California San DiegoBioinformatics and Systems Biology Program, University of California San DiegoCenter for Personalized Cancer Therapy, Division of Hematology and Oncology, UC San Diego Moores Cancer CenterDepartment of Cellular and Molecular Medicine, University of California San DiegoMoores Cancer Center, University of California San DiegoMoores Cancer Center, University of California San DiegoLaboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health (NIH)Center for Population Neuroscience and Genetics, Laureate Institute for Brain ResearchDivision of Biostatistics, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San DiegoLaboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health (NIH)Department of Pharmacology, UCSD Moores Cancer CenterLa Jolla Institute for ImmunologyMoores Cancer Center, University of California San DiegoAbstract With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.https://doi.org/10.1038/s41467-023-38271-5 |
| spellingShingle | Meghana Pagadala Timothy J. Sears Victoria H. Wu Eva Pérez-Guijarro Hyo Kim Andrea Castro James V. Talwar Cristian Gonzalez-Colin Steven Cao Benjamin J. Schmiedel Shervin Goudarzi Divya Kirani Jessica Au Tongwu Zhang Teresa Landi Rany M. Salem Gerald P. Morris Olivier Harismendy Sandip Pravin Patel Ludmil B. Alexandrov Jill P. Mesirov Maurizio Zanetti Chi-Ping Day Chun Chieh Fan Wesley K. Thompson Glenn Merlino J. Silvio Gutkind Pandurangan Vijayanand Hannah Carter Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response Nature Communications |
| title | Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response |
| title_full | Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response |
| title_fullStr | Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response |
| title_full_unstemmed | Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response |
| title_short | Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response |
| title_sort | germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response |
| url | https://doi.org/10.1038/s41467-023-38271-5 |
| work_keys_str_mv | AT meghanapagadala germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT timothyjsears germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT victoriahwu germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT evaperezguijarro germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT hyokim germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT andreacastro germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT jamesvtalwar germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT cristiangonzalezcolin germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT stevencao germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT benjaminjschmiedel germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT shervingoudarzi germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT divyakirani germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT jessicaau germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT tongwuzhang germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT teresalandi germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT ranymsalem germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT geraldpmorris germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT olivierharismendy germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT sandippravinpatel germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT ludmilbalexandrov germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT jillpmesirov germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT mauriziozanetti germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT chipingday germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT chunchiehfan germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT wesleykthompson germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT glennmerlino germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT jsilviogutkind germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT panduranganvijayanand germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse AT hannahcarter germlinemodifiersofthetumorimmunemicroenvironmentimplicatedriversofcancerriskandimmunotherapyresponse |