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Molecular patterns of resistance to immune checkpoint blockade in melanoma

Author

Listed:
  • Martin Lauss

    (Lund University
    LUCC)

  • Bengt Phung

    (Lund University
    LUCC)

  • Troels Holz Borch

    (Copenhagen University Hospital)

  • Katja Harbst

    (Lund University
    LUCC)

  • Kamila Kaminska

    (Lund University
    LUCC)

  • Anna Ebbesson

    (Lund University
    LUCC)

  • Ingrid Hedenfalk

    (Lund University
    LUCC)

  • Joan Yuan

    (Lund University)

  • Kari Nielsen

    (LUCC
    Lund University)

  • Christian Ingvar

    (Lund University)

  • Ana Carneiro

    (Lund University
    Skåne University Hospital Comprehensive Cancer Center)

  • Karolin Isaksson

    (LUCC
    Lund University
    Kristianstad Hospital)

  • Kristian Pietras

    (LUCC
    Lund University)

  • Inge Marie Svane

    (Copenhagen University Hospital)

  • Marco Donia

    (Copenhagen University Hospital)

  • Göran Jönsson

    (Lund University
    LUCC)

Abstract

Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collect biopsies from a cohort of 44 patients with melanoma after progression on anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways are observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions have a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and T cell receptor (TCR) clonality analyses. One anti-PD1 resistant lesion harbors a distinct immune cell niche, however, anti-PD1 resistant tumors are generally immune poor with non-expanded TCR clones. Such immune poor microenvironments are associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors have reduced fractions of PD1+ CD8+ T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.

Suggested Citation

  • Martin Lauss & Bengt Phung & Troels Holz Borch & Katja Harbst & Kamila Kaminska & Anna Ebbesson & Ingrid Hedenfalk & Joan Yuan & Kari Nielsen & Christian Ingvar & Ana Carneiro & Karolin Isaksson & Kri, 2024. "Molecular patterns of resistance to immune checkpoint blockade in melanoma," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47425-y
    DOI: 10.1038/s41467-024-47425-y
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    as
    1. Keith A. Lawson & Cristovão M. Sousa & Xiaoyu Zhang & Eiru Kim & Rummy Akthar & Joseph J. Caumanns & Yuxi Yao & Nicholas Mikolajewicz & Catherine Ross & Kevin R. Brown & Abdelrahman Abou Zid & Zi Peng, 2020. "Functional genomic landscape of cancer-intrinsic evasion of killing by T cells," Nature, Nature, vol. 586(7827), pages 120-126, October.
    2. Rita Cabrita & Martin Lauss & Adriana Sanna & Marco Donia & Mathilde Skaarup Larsen & Shamik Mitra & Iva Johansson & Bengt Phung & Katja Harbst & Johan Vallon-Christersson & Alison Schoiack & Kristina, 2020. "Author Correction: Tertiary lymphoid structures improve immunotherapy and survival in melanoma," Nature, Nature, vol. 580(7801), pages 1-1, April.
    3. Panagiotis Karras & Ignacio Bordeu & Joanna Pozniak & Ada Nowosad & Cecilia Pazzi & Nina Raemdonck & Ewout Landeloos & Yannick Herck & Dennis Pedri & Greet Bervoets & Samira Makhzami & Jia Hui Khoo & , 2022. "A cellular hierarchy in melanoma uncouples growth and metastasis," Nature, Nature, vol. 610(7930), pages 190-198, October.
    4. Sanjeev Mariathasan & Shannon J. Turley & Dorothee Nickles & Alessandra Castiglioni & Kobe Yuen & Yulei Wang & Edward E. Kadel III & Hartmut Koeppen & Jillian L. Astarita & Rafael Cubas & Suchit Jhunj, 2018. "TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells," Nature, Nature, vol. 554(7693), pages 544-548, February.
    5. 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.
    6. Mikhail Shugay & Dmitriy V Bagaev & Maria A Turchaninova & Dmitriy A Bolotin & Olga V Britanova & Ekaterina V Putintseva & Mikhail V Pogorelyy & Vadim I Nazarov & Ivan V Zvyagin & Vitalina I Kirgizova, 2015. "VDJtools: Unifying Post-analysis of T Cell Receptor Repertoires," PLOS Computational Biology, Public Library of Science, vol. 11(11), pages 1-16, November.
    7. Ludmil B. Alexandrov & Serena Nik-Zainal & David C. Wedge & Samuel A. J. R. Aparicio & Sam Behjati & Andrew V. Biankin & Graham R. Bignell & Niccolò Bolli & Ake Borg & Anne-Lise Børresen-Dale & Sandri, 2013. "Correction: Corrigendum: Signatures of mutational processes in human cancer," Nature, Nature, vol. 502(7470), pages 258-258, October.
    8. Rita Cabrita & Martin Lauss & Adriana Sanna & Marco Donia & Mathilde Skaarup Larsen & Shamik Mitra & Iva Johansson & Bengt Phung & Katja Harbst & Johan Vallon-Christersson & Alison Schoiack & Kristina, 2020. "Tertiary lymphoid structures improve immunotherapy and survival in melanoma," Nature, Nature, vol. 577(7791), pages 561-565, January.
    9. Moshe Sade-Feldman & Yunxin J. Jiao & Jonathan H. Chen & Michael S. Rooney & Michal Barzily-Rokni & Jean-Pierre Eliane & Stacey L. Bjorgaard & Marc R. Hammond & Hans Vitzthum & Shauna M. Blackmon & De, 2017. "Resistance to checkpoint blockade therapy through inactivation of antigen presentation," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    10. Panagiotis Karras & Ignacio Bordeu & Joanna Pozniak & Ada Nowosad & Cecilia Pazzi & Nina Raemdonck & Ewout Landeloos & Yannick Herck & Dennis Pedri & Greet Bervoets & Samira Makhzami & Jia Hui Khoo & , 2022. "Author Correction: A cellular hierarchy in melanoma uncouples growth and metastasis," Nature, Nature, vol. 611(7934), pages 4-4, November.
    11. Shashank J. Patel & Neville E. Sanjana & Rigel J. Kishton & Arash Eidizadeh & Suman K. Vodnala & Maggie Cam & Jared J. Gartner & Li Jia & Seth M. Steinberg & Tori N. Yamamoto & Anand S. Merchant & Gau, 2017. "Identification of essential genes for cancer immunotherapy," Nature, Nature, vol. 548(7669), pages 537-542, August.
    12. Robert T. Manguso & Hans W. Pope & Margaret D. Zimmer & Flavian D. Brown & Kathleen B. Yates & Brian C. Miller & Natalie B. Collins & Kevin Bi & Martin W. LaFleur & Vikram R. Juneja & Sarah A. Weiss &, 2017. "In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target," Nature, Nature, vol. 547(7664), pages 413-418, July.
    13. 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.
    14. Shohei Koyama & Esra A. Akbay & Yvonne Y. Li & Grit S. Herter-Sprie & Kevin A. Buczkowski & William G. Richards & Leena Gandhi & Amanda J. Redig & Scott J. Rodig & Hajime Asahina & Robert E. Jones & M, 2016. "Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints," Nature Communications, Nature, vol. 7(1), pages 1-9, April.
    15. Ludmil B. Alexandrov & Serena Nik-Zainal & David C. Wedge & Samuel A. J. R. Aparicio & Sam Behjati & Andrew V. Biankin & Graham R. Bignell & Niccolò Bolli & Ake Borg & Anne-Lise Børresen-Dale & Sandri, 2013. "Signatures of mutational processes in human cancer," Nature, Nature, vol. 500(7463), pages 415-421, August.
    16. Beth A. Helmink & Sangeetha M. Reddy & Jianjun Gao & Shaojun Zhang & Rafet Basar & Rohit Thakur & Keren Yizhak & Moshe Sade-Feldman & Jorge Blando & Guangchun Han & Vancheswaran Gopalakrishnan & Yuanx, 2020. "B cells and tertiary lymphoid structures promote immunotherapy response," Nature, Nature, vol. 577(7791), pages 549-555, January.
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