Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility

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 and Udai S. Kammula ()
Additional contact information
Shravan Leonard-Murali: University of Pittsburgh
Chetana Bhaskarla: University of Pittsburgh
Ghanshyam S. Yadav: University of Pittsburgh
Sudeep K. Maurya: University of Pittsburgh
Chenna R. Galiveti: University of Pittsburgh
Joshua A. Tobin: University of Pittsburgh
Rachel J. Kann: University of Pittsburgh
Eishan Ashwat: University of Pittsburgh
Patrick S. Murphy: University of Pittsburgh
Anish B. Chakka: University of Pittsburgh
Vishal Soman: University of Pittsburgh
Paul G. Cantalupo: University of Pittsburgh
Xinming Zhuo: University of Pittsburgh
Gopi Vyas: University of Pittsburgh
Dara L. Kozak: University of Pittsburgh
Lindsey M. Kelly: University of Pittsburgh
Ed Smith: University of Pittsburgh
Uma R. Chandran: University of Pittsburgh
Yen-Michael S. Hsu: University of Pittsburgh
Udai S. Kammula: University of Pittsburgh

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46906-4

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