Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility
Abstract Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melano...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46906-4 |
| _version_ | 1797199356520038400 |
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| author | Shravan Leonard-Murali Chetana Bhaskarla Ghanshyam S. Yadav Sudeep K. Maurya Chenna R. Galiveti Joshua A. Tobin Rachel J. Kann Eishan Ashwat Patrick S. Murphy Anish B. Chakka Vishal Soman Paul G. Cantalupo Xinming Zhuo Gopi Vyas Dara L. Kozak Lindsey M. Kelly Ed Smith Uma R. Chandran Yen-Michael S. Hsu Udai S. Kammula |
| author_facet | Shravan Leonard-Murali Chetana Bhaskarla Ghanshyam S. Yadav Sudeep K. Maurya Chenna R. Galiveti Joshua A. Tobin Rachel J. Kann Eishan Ashwat Patrick S. Murphy Anish B. Chakka Vishal Soman Paul G. Cantalupo Xinming Zhuo Gopi Vyas Dara L. Kozak Lindsey M. Kelly Ed Smith Uma R. Chandran Yen-Michael S. Hsu Udai S. Kammula |
| author_sort | Shravan Leonard-Murali |
| collection | DOAJ |
| description | Abstract Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable. |
| first_indexed | 2024-04-24T07:14:27Z |
| format | Article |
| id | doaj.art-c3827bd8a22341ebb07936043ec06ea7 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T07:14:27Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-c3827bd8a22341ebb07936043ec06ea72024-04-21T11:23:09ZengNature PortfolioNature Communications2041-17232024-04-0115111710.1038/s41467-024-46906-4Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibilityShravan Leonard-Murali0Chetana Bhaskarla1Ghanshyam S. Yadav2Sudeep K. Maurya3Chenna R. Galiveti4Joshua A. Tobin5Rachel J. Kann6Eishan Ashwat7Patrick S. Murphy8Anish B. Chakka9Vishal Soman10Paul G. Cantalupo11Xinming Zhuo12Gopi Vyas13Dara L. Kozak14Lindsey M. Kelly15Ed Smith16Uma R. Chandran17Yen-Michael S. Hsu18Udai S. Kammula19UPMC Hillman Cancer Center, University of PittsburghUPMC Hillman Cancer Center, University of PittsburghUPMC Hillman Cancer Center, University of PittsburghUPMC Hillman Cancer Center, University of PittsburghUPMC Hillman Cancer Center, University of PittsburghUPMC Hillman Cancer Center, University of PittsburghUPMC Hillman Cancer Center, University of PittsburghUPMC Hillman Cancer Center, University of PittsburghUPMC Hillman Cancer Center, University of PittsburghDepartment of Biomedical Informatics, University of PittsburghDepartment of Biomedical Informatics, University of PittsburghDepartment of Biomedical Informatics, University of PittsburghUPMC Genome Center, University of PittsburghUPMC Genome Center, University of PittsburghUPMC Genome Center, University of PittsburghUPMC Genome Center, University of PittsburghUPMC Genome Center, University of PittsburghUPMC Hillman Cancer Center, University of PittsburghUPMC Hillman Cancer Center, University of PittsburghUPMC Hillman Cancer Center, University of PittsburghAbstract Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable.https://doi.org/10.1038/s41467-024-46906-4 |
| spellingShingle | Shravan Leonard-Murali Chetana Bhaskarla Ghanshyam S. Yadav Sudeep K. Maurya Chenna R. Galiveti Joshua A. Tobin Rachel J. Kann Eishan Ashwat Patrick S. Murphy Anish B. Chakka Vishal Soman Paul G. Cantalupo Xinming Zhuo Gopi Vyas Dara L. Kozak Lindsey M. Kelly Ed Smith Uma R. Chandran Yen-Michael S. Hsu Udai S. Kammula Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility Nature Communications |
| title | Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility |
| title_full | Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility |
| title_fullStr | Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility |
| title_full_unstemmed | Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility |
| title_short | Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility |
| title_sort | uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility |
| url | https://doi.org/10.1038/s41467-024-46906-4 |
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