IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-46906-4.html
   My bibliography  Save this article

Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility

Author

Listed:
  • Shravan Leonard-Murali

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Chetana Bhaskarla

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Ghanshyam S. Yadav

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Sudeep K. Maurya

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Chenna R. Galiveti

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Joshua A. Tobin

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Rachel J. Kann

    (University of Pittsburgh)

  • Eishan Ashwat

    (University of Pittsburgh)

  • Patrick S. Murphy

    (University of Pittsburgh
    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
    University of Pittsburgh)

  • Yen-Michael S. Hsu

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Udai S. Kammula

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

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.

Suggested Citation

  • 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 & Visha, 2024. "Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46906-4
    DOI: 10.1038/s41467-024-46906-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-46906-4
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-46906-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Michael A. Durante & Daniel A. Rodriguez & Stefan Kurtenbach & Jeffim N. Kuznetsov & Margaret I. Sanchez & Christina L. Decatur & Helen Snyder & Lynn G. Feun & Alan S. Livingstone & J. William Harbour, 2020. "Single-cell analysis reveals new evolutionary complexity in uveal melanoma," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    2. Matthew G. Field & Michael A. Durante & Hima Anbunathan & Louis Z. Cai & Christina L. Decatur & Anne M. Bowcock & Stefan Kurtenbach & J. William Harbour, 2018. "Punctuated evolution of canonical genomic aberrations in uveal melanoma," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    3. Daniel C. Jeffares & Clemency Jolly & Mimoza Hoti & Doug Speed & Liam Shaw & Charalampos Rallis & Francois Balloux & Christophe Dessimoz & Jürg Bähler & Fritz J. Sedlazeck, 2017. "Transient structural variations have strong effects on quantitative traits and reproductive isolation in fission yeast," Nature Communications, Nature, vol. 8(1), pages 1-11, April.
    4. Paul C. Tumeh & Christina L. Harview & Jennifer H. Yearley & I. Peter Shintaku & Emma J. M. Taylor & Lidia Robert & Bartosz Chmielowski & Marko Spasic & Gina Henry & Voicu Ciobanu & Alisha N. West & M, 2014. "PD-1 blockade induces responses by inhibiting adaptive immune resistance," Nature, Nature, vol. 515(7528), pages 568-571, November.
    5. Stefani Spranger & Riyue Bao & Thomas F. Gajewski, 2015. "Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity," Nature, Nature, vol. 523(7559), pages 231-235, July.
    6. Jun Chen & Ming-Chao Zhong & Huaijian Guo & Dominique Davidson & Sabrin Mishel & Yan Lu & Inmoo Rhee & Luis-Alberto Pérez-Quintero & Shaohua Zhang & Mario-Ernesto Cruz-Munoz & Ning Wu & Donald C. Vinh, 2017. "SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin," Nature, Nature, vol. 544(7651), pages 493-497, April.
    7. Joyce B. Kang & Aparna Nathan & Kathryn Weinand & Fan Zhang & Nghia Millard & Laurie Rumker & D. Branch Moody & Ilya Korsunsky & Soumya Raychaudhuri, 2021. "Efficient and precise single-cell reference atlas mapping with Symphony," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Jani Huuhtanen & Liang Chen & Emmi Jokinen & Henna Kasanen & Tapio Lönnberg & Anna Kreutzman & Katriina Peltola & Micaela Hernberg & Chunlin Wang & Cassian Yee & Harri Lähdesmäki & Mark M. Davis & Sat, 2022. "Evolution and modulation of antigen-specific T cell responses in melanoma patients," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Jodi M. Carter & Saranya Chumsri & Douglas A. Hinerfeld & Yaohua Ma & Xue Wang & David Zahrieh & David W. Hillman & Kathleen S. Tenner & Jennifer M. Kachergus & Heather Ann Brauer & Sarah E. Warren & , 2023. "Distinct spatial immune microlandscapes are independently associated with outcomes in triple-negative breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Heng Du & Lei Zhou & Zhen Liu & Yue Zhuo & Meilin Zhang & Qianqian Huang & Shiyu Lu & Kai Xing & Li Jiang & Jian-Feng Liu, 2024. "The 1000 Chinese Indigenous Pig Genomes Project provides insights into the genomic architecture of pigs," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Aditi Sahu & Kivanc Kose & Lukas Kraehenbuehl & Candice Byers & Aliya Holland & Teguru Tembo & Anthony Santella & Anabel Alfonso & Madison Li & Miguel Cordova & Melissa Gill & Christi Fox & Salvador G, 2022. "In vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    5. Chunping Mao & Fuan Deng & Wanning Zhu & Leiming Xie & Yijun Wang & Guoyin Li & Xingke Huang & Jiahui Wang & Yue Song & Ping Zeng & Zhenpeng He & Jingnan Guo & Yao Suo & Yujing Liu & Zhuo Chen & Mingx, 2024. "In situ editing of tumour cell membranes induces aggregation and capture of PD-L1 membrane proteins for enhanced cancer immunotherapy," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    6. Liyuan Zhou & Qiongzi Qiu & Qing Zhou & Jianwei Li & Mengqian Yu & Kezhen Li & Lingling Xu & Xiaohui Ke & Haiming Xu & Bingjian Lu & Hui Wang & Weiguo Lu & Pengyuan Liu & Yan Lu, 2022. "Long-read sequencing unveils high-resolution HPV integration and its oncogenic progression in cervical cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    7. Yu Feng & Wenjuan Ma & Yupeng Zang & Yanying Guo & Young Li & Yixuan Zhang & Xuan Dong & Yi Liu & Xiaojuan Zhan & Zhizhong Pan & Mei Luo & Miaoqing Wu & Ao Chen & Da Kang & Gong Chen & Longqi Liu & Ji, 2024. "Spatially organized tumor-stroma boundary determines the efficacy of immunotherapy in colorectal cancer patients," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    8. Jinhyun Kim & Sungsik Kim & Huiran Yeom & Seo Woo Song & Kyoungseob Shin & Sangwook Bae & Han Suk Ryu & Ji Young Kim & Ahyoun Choi & Sumin Lee & Taehoon Ryu & Yeongjae Choi & Hamin Kim & Okju Kim & Yu, 2023. "Barcoded multiple displacement amplification for high coverage sequencing in spatial genomics," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    9. Elaine Lai-Han Leung & Run-Ze Li & Xing-Xing Fan & Lily Yan Wang & Yan Wang & Zebo Jiang & Jumin Huang & Hu-Dan Pan & Yue Fan & Hongmei Xu & Feng Wang & Haopeng Rui & Piu Wong & Hermi Sumatoh & Michae, 2023. "Longitudinal high-dimensional analysis identifies immune features associating with response to anti-PD-1 immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    10. Rana Falahat & Anders Berglund & Patricio Perez-Villarroel & Ryan M. Putney & Imene Hamaidi & Sungjune Kim & Shari Pilon-Thomas & Glen N. Barber & James J. Mulé, 2023. "Epigenetic state determines the in vivo efficacy of STING agonist therapy," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    11. Yingyan Yu & Zhen Zhang & Xiaorui Dong & Ruixin Yang & Zhongqu Duan & Zhen Xiang & Jun Li & Guichao Li & Fazhe Yan & Hongzhang Xue & Du Jiao & Jinyuan Lu & Huimin Lu & Wenmin Zhang & Yangzhen Wei & Sh, 2022. "Pangenomic analysis of Chinese gastric cancer," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    12. Huiying He & Yue Leng & Xinglan Cao & Yiwang Zhu & Xiaoxia Li & Qiaoling Yuan & Bin Zhang & Wenchuang He & Hua Wei & Xiangpei Liu & Qiang Xu & Mingliang Guo & Hong Zhang & Longbo Yang & Yang Lv & Xian, 2024. "The pan-tandem repeat map highlights multiallelic variants underlying gene expression and agronomic traits in rice," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    13. Tian-mei Zeng & Guang Yang & Cheng Lou & Wei Wei & Chen-jie Tao & Xi-yun Chen & Qin Han & Zhuo Cheng & Pei-pei Shang & Yu-long Dong & He-ming Xu & Lie-ping Guo & Dong-sheng Chen & Yun-jie Song & Chuan, 2023. "Clinical and biomarker analyses of sintilimab plus gemcitabine and cisplatin as first-line treatment for patients with advanced biliary tract cancer," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    14. Junmeng Zhu & Yaohua Ke & Qin Liu & Ju Yang & Fangcen Liu & Ruihan Xu & Hang Zhou & Aoxing Chen & Jie Xiao & Fanyan Meng & Lixia Yu & Rutian Li & Jia Wei & Baorui Liu, 2022. "Engineered Lactococcus lactis secreting Flt3L and OX40 ligand for in situ vaccination-based cancer immunotherapy," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    15. Su Yin Lim & Elena Shklovskaya & Jenny H. Lee & Bernadette Pedersen & Ashleigh Stewart & Zizhen Ming & Mal Irvine & Brindha Shivalingam & Robyn P. M. Saw & Alexander M. Menzies & Matteo S. Carlino & R, 2023. "The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    16. Stefano Pierini & Rashid Gabbasov & Maria Cecilia Oliveira-Nunes & Rehman Qureshi & Alison Worth & Shuo Huang & Karan Nagar & Crystal Griffin & Lurong Lian & Yumi Yashiro-Ohtani & Kayleigh Ross & Chri, 2025. "Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade in pre-clinical models," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    17. Markus Haake & Beatrice Haack & Tina Schäfer & Patrick N. Harter & Greta Mattavelli & Patrick Eiring & Neha Vashist & Florian Wedekink & Sabrina Genssler & Birgitt Fischer & Julia Dahlhoff & Fatemeh M, 2023. "Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    18. Tuomas Hämälä & Christopher Moore & Laura Cowan & Matthew Carlile & David Gopaulchan & Marie K. Brandrud & Siri Birkeland & Matthew Loose & Filip Kolář & Marcus A. Koch & Levi Yant, 2024. "Impact of whole-genome duplications on structural variant evolution in Cochlearia," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    19. Kuang Du & Shiyou Wei & Zhi Wei & Dennie T. Frederick & Benchun Miao & Tabea Moll & Tian Tian & Eric Sugarman & Dmitry I. Gabrilovich & Ryan J. Sullivan & Lunxu Liu & Keith T. Flaherty & Genevieve M. , 2021. "Pathway signatures derived from on-treatment tumor specimens predict response to anti-PD1 blockade in metastatic melanoma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    20. Darci Phillips & Magdalena Matusiak & Belén Rivero Gutierrez & Salil S. Bhate & Graham L. Barlow & Sizun Jiang & Janos Demeter & Kimberly S. Smythe & Robert H. Pierce & Steven P. Fling & Nirasha Ramch, 2021. "Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma," Nature Communications, Nature, vol. 12(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46906-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.