Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility

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 metast...

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Bibliographic Details
Published in:	Nature communications Vol. 15; no. 1; p. 2863
Main Authors:	Leonard-Murali, Shravan, Bhaskarla, Chetana, Yadav, Ghanshyam S., Maurya, Sudeep K., Galiveti, Chenna R., Tobin, Joshua A., Kann, Rachel J., Ashwat, Eishan, Murphy, Patrick S., Chakka, Anish B., Soman, Vishal, Cantalupo, Paul G., Zhuo, Xinming, Vyas, Gopi, Kozak, Dara L., Kelly, Lindsey M., Smith, Ed, Chandran, Uma R., Hsu, Yen-Michael S., Kammula, Udai S.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 16-04-2024 Nature Publishing Group Nature Portfolio
Subjects:	13/106 13/31 45/23 45/91 631/67/1857 631/67/322 631/67/580 692/4028/546 692/4028/67/69 Adoptive transfer Biomarkers Humanities and Social Sciences Humans Immune checkpoint inhibitors Immune privilege Immunity Immunotherapy Lymphocytes Lymphocytes T Lymphocytes, Tumor-Infiltrating Melanoma Melanoma - genetics Melanoma - therapy Metastases Metastasis multidisciplinary Science Science (multidisciplinary) Skin Neoplasms T cell receptors Transcriptomics Tumor microenvironment Tumor Microenvironment - genetics Tumors Uveal Neoplasms - genetics Uveal Neoplasms - therapy
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Summary:	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. Metastatic uveal melanoma is poorly responsive to immune checkpoint inhibition. Here, the authors analyse 100 uveal melanoma metastases using bulk and single cell RNA-seq, TCR analysis, and immune reactivity to show potent, yet, quiescent tumour infiltrating lymphocytes that can be harnessed by adoptive transfer to confer tumour immunity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-46906-4