IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-65025-2.html
   My bibliography  Save this article

Anti-PD-L2 immunotherapy is efficacious against melanoma in aged hosts through IL-17 and IFNγ signalling

Author

Listed:
  • Carlos O. Ontiveros

    (University of Texas Health, South Texas Medical Scientist Training Program
    University of Texas Health, Graduate School of Biomedical Sciences
    University of Texas Health, Department of Medicine)

  • Myrna G. Garcia

    (University of Texas Health, South Texas Medical Scientist Training Program
    University of Texas Health, Graduate School of Biomedical Sciences
    University of Texas Health, Department of Medicine)

  • Clare E. Murray

    (University of Texas Health, South Texas Medical Scientist Training Program
    University of Texas Health, Graduate School of Biomedical Sciences
    University of Texas Health, Department of Medicine)

  • Yilun Deng

    (University of Texas Health, Department of Medicine)

  • Haiyan Bai

    (Dartmouth Health)

  • Christopher Tanner

    (Geisel School of Medicine at Dartmouth College, Department of Microbiology and Immunology)

  • Bernice Leung

    (Geisel School of Medicine at Dartmouth College, Department of Microbiology and Immunology)

  • Xin Li

    (Geisel School of Medicine at Dartmouth College, Department of Microbiology and Immunology)

  • Alvaro Padron

    (University of Texas Health, Department of Medicine)

  • Ryan M. Reyes

    (University of Texas Health, South Texas Medical Scientist Training Program
    University of Texas Health, Graduate School of Biomedical Sciences
    University of Texas Health, Department of Medicine)

  • Aravind Kancharla

    (University of Texas Health, Department of Medicine
    Senda Biosciences, AK)

  • Kah Teong Soh

    (Agenus)

  • Shanmugarajan Krishnan

    (Agenus)

  • Dhan Chand

    (Agenus)

  • Akshaya Balasubramanian

    (Geisel School of Medicine at Dartmouth College, Department of Microbiology and Immunology)

  • Courtney Hegner

    (The Scripps Research Institute)

  • Claudia V. Jakubzick

    (Dartmouth, Geisel School of Medicine at Dartmouth)

  • Harshita B. Gupta

    (University of Texas Health, Department of Medicine)

  • Mary Jo Turk

    (Geisel School of Medicine at Dartmouth College, Department of Microbiology and Immunology
    Dartmouth Cancer Center)

  • Mark Sundrud

    (Dartmouth Health
    Geisel School of Medicine at Dartmouth College, Department of Microbiology and Immunology
    Dartmouth, Geisel School of Medicine at Dartmouth
    Dartmouth Cancer Center)

  • Jose R. Conejo-Garcia

    (Duke University)

  • Tyler J. Curiel

    (University of Texas Health, South Texas Medical Scientist Training Program
    University of Texas Health, Graduate School of Biomedical Sciences
    University of Texas Health, Department of Medicine
    Dartmouth Health)

Abstract

The PD-L1 immune checkpoint ligates the PD-1 immune checkpoint, and antibodies against either are effective in treating selected human cancers. Although PD-L2 also ligates PD-1, αPD-L2 is little studied as cancer immunotherapy. We previously showed that αPD-L1 treated young B16-bearing mice but failed in aged. We show here that αPD-L2 fails in young B16-bearing mice but is effective in aged. αPD-L2 increases tumour-infiltrating interferon-γ+ immune cell prevalence and interferon-γ production in aged but not young melanoma-bearing hosts in an unexpectedly IL-17-dependent manner. We also show improved αPD-L2 efficacy with advancing age in another tumour type, and αPD-L2-responsive tumours in young hosts, but without IL-17 dependence. The immune B16 microenvironment in aged IL-17-deficient hosts resembles that of young hosts, and exogenous IL-17 elicits αPD-L2 melanoma efficacy in young hosts, demonstrating IL-17 influence on aged immune outcomes. Mechanistic insights into age-related αPD-L2 efficacy could improve immune checkpoint blockade efficacy including in younger patients, address immune checkpoint blockade-resistant tumours and improve understanding of age effects on anti-cancer immunity.

Suggested Citation

  • Carlos O. Ontiveros & Myrna G. Garcia & Clare E. Murray & Yilun Deng & Haiyan Bai & Christopher Tanner & Bernice Leung & Xin Li & Alvaro Padron & Ryan M. Reyes & Aravind Kancharla & Kah Teong Soh & Sh, 2025. "Anti-PD-L2 immunotherapy is efficacious against melanoma in aged hosts through IL-17 and IFNγ signalling," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65025-2
    DOI: 10.1038/s41467-025-65025-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-65025-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-65025-2?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. Weimin Wang & Michael Green & Jae Eun Choi & Miguel Gijón & Paul D. Kennedy & Jeffrey K. Johnson & Peng Liao & Xueting Lang & Ilona Kryczek & Amanda Sell & Houjun Xia & Jiajia Zhou & Gaopeng Li & Jing, 2019. "CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy," Nature, Nature, vol. 569(7755), pages 270-274, May.
    2. Seth B. Coffelt & Kelly Kersten & Chris W. Doornebal & Jorieke Weiden & Kim Vrijland & Cheei-Sing Hau & Niels J. M. Verstegen & Metamia Ciampricotti & Lukas J. A. C. Hawinkels & Jos Jonkers & Karin E., 2015. "IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis," Nature, Nature, vol. 522(7556), pages 345-348, June.
    3. Amanpreet Kaur & Marie R. Webster & Katie Marchbank & Reeti Behera & Abibatou Ndoye & Curtis H. Kugel & Vanessa M. Dang & Jessica Appleton & Michael P. O’Connell & Phil Cheng & Alexander A. Valiga & R, 2016. "RETRACTED ARTICLE: sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance," Nature, Nature, vol. 532(7598), pages 250-254, April.
    4. Amanpreet Kaur & Marie R. Webster & Katie Marchbank & Reeti Behera & Abibatou Ndoye & Curtis H. Kugel & Vanessa M. Dang & Jessica Appleton & Michael P. O’Connell & Phil Cheng & Alexander A. Valiga & R, 2016. "Correction: Corrigendum: sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance," Nature, Nature, vol. 537(7619), pages 254-254, September.
    5. Vijay Shankaran & Hiroaki Ikeda & Allen T. Bruce & J. Michael White & Paul E. Swanson & Lloyd J. Old & Robert D. Schreiber, 2001. "IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity," Nature, Nature, vol. 410(6832), pages 1107-1111, April.
    6. Joon Seok Park & Francesca S. Gazzaniga & Meng Wu & Amalia K. Luthens & Jacob Gillis & Wen Zheng & Martin W. LaFleur & Sarah B. Johnson & Golnaz Morad & Elizabeth M. Park & Yifan Zhou & Stephanie S. W, 2023. "Targeting PD-L2–RGMb overcomes microbiome-related immunotherapy resistance," Nature, Nature, vol. 617(7960), pages 377-385, May.
    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. Runping Duan & Loujing Jiang & Tianfu Wang & Zhaohuai Li & Xiaoyang Yu & Yuehan Gao & Renbing Jia & Xianqun Fan & Wenru Su, 2024. "Aging-induced immune microenvironment remodeling fosters melanoma in male mice via γδ17-Neutrophil-CD8 axis," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Damien Maggiorani & Oanh Le & Véronique Lisi & Séverine Landais & Gaël Moquin-Beaudry & Vincent Philippe Lavallée & Hélène Decaluwe & Christian Beauséjour, 2024. "Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Miranda V. Hunter & Reuben Moncada & Joshua M. Weiss & Itai Yanai & Richard M. White, 2021. "Spatially resolved transcriptomics reveals the architecture of the tumor-microenvironment interface," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    4. Jayanta Mondal & Junfeng Zhang & Feng Qing & Shunping Li & Dhiraj Kumar & Jason T. Huse & Filippo G. Giancotti, 2025. "Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    5. Juan Cheng & Siqi Zhang & Qian Gui & Zedan Pu & Zhiyu Chen & Quanfang Wei & Hongbo Qi & Jianxiang Zhang, 2025. "Identifying fibroblast-derived sFRP2 as a therapeutic target and engineering siRNA therapy for uterine scarring," Nature Communications, Nature, vol. 16(1), pages 1-24, December.
    6. Wenqing Xu & Guanheng Huang & Zhan Yang & Ziqi Deng & Chen Zhou & Jian-An Li & Ming-De Li & Tao Hu & Ben Zhong Tang & David Lee Phillips, 2024. "Nucleic-acid-base photofunctional cocrystal for information security and antimicrobial applications," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    7. Sara Orehek & Taja Železnik Ramuta & Duško Lainšček & Špela Malenšek & Martin Šala & Mojca Benčina & Roman Jerala & Iva Hafner-Bratkovič, 2024. "Cytokine-armed pyroptosis induces antitumor immunity against diverse types of tumors," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    8. Di-Yang Sun & Wen-Bin Wu & Jian-Jin Wu & Yu Shi & Jia-Jun Xu & Shen-Xi Ouyang & Chen Chi & Yi Shi & Qing-Xin Ji & Jin-Hao Miao & Jiang-Tao Fu & Jie Tong & Ping-Ping Zhang & Jia-Bao Zhang & Zhi-Yong Li, 2024. "Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    9. Junho Lee & Donggu Lee & Sean Lawler & Yangjin Kim, 2021. "Role of neutrophil extracellular traps in regulation of lung cancer invasion and metastasis: Structural insights from a computational model," PLOS Computational Biology, Public Library of Science, vol. 17(2), pages 1-29, February.
    10. Li-Kai Chu & Xu Cao & Lin Wan & Qiang Diao & Yu Zhu & Yu Kan & Li-Li Ye & Yi-Ming Mao & Xing-Qiang Dong & Qian-Wei Xiong & Ming-Cui Fu & Ting Zhang & Hui-Ting Zhou & Shi-Zhong Cai & Zhou-Rui Ma & Ssu-, 2023. "Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    11. Charlotte R. Bell & Victoria S. Pelly & Agrin Moeini & Shih-Chieh Chiang & Eimear Flanagan & Christian P. Bromley & Christopher Clark & Charles H. Earnshaw & Maria A. Koufaki & Eduardo Bonavita & Sant, 2022. "Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    12. Ying Xue & Fujia Lu & Zhenzhen Chang & Jing Li & Yuan Gao & Jie Zhou & Ying Luo & Yongfeng Lai & Siyuan Cao & Xiaoxiao Li & Yuhan Zhou & Yan Li & Zheng Tan & Xiang Cheng & Xiong Li & Jing Chen & Weimi, 2023. "Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    13. Zhigui Zuo & Hao Yin & Yu Zhang & Congying Xie & Qinyang Wang, 2023. "A cytotoxic T cell inspired oncolytic nanosystem promotes lytic cell death by lipid peroxidation and elicits antitumor immune responses," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. Mingming Wu & Xiao Zhang & Weijie Zhang & Yi Shiou Chiou & Wenchang Qian & Xiangtian Liu & Min Zhang & Hong Yan & Shilan Li & Tao Li & Xinghua Han & Pengxu Qian & Suling Liu & Yueyin Pan & Peter E. Lo, 2022. "Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    15. Da Teng & Kenneth D. Swanson & Ruiheng Wang & Aojia Zhuang & Haofeng Wu & Zhixin Niu & Li Cai & Faith R. Avritt & Lei Gu & John M. Asara & Yaqing Zhang & Bin Zheng, 2025. "DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    16. Jian Cao & Xuan Zhu & Xiaokun Zhao & Xue-Feng Li & Ran Xu, 2016. "Neutrophil-to-Lymphocyte Ratio Predicts PSA Response and Prognosis in Prostate Cancer: A Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 11(7), pages 1-15, July.
    17. Ruolin Li & Wenjin Luo & Xiangjun Chen & Qinglian Zeng & Shumin Yang & Ping Wang & Jinbo Hu & Aijun Chen, 2024. "An observational and genetic investigation into the association between psoriasis and risk of malignancy," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    18. Weifan Lin & Wuheng Huang & Shiqiang Mei & Xiangwan Lu & Junheng Zheng & Hua Wang & Lingling Zheng & Yan Zhang, 2025. "Transdifferentiation of tongue muscle cells into cancer-associated fibroblasts in response to tongue squamous cell carcinoma," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    19. Dadi Jiang & Youming Guo & Tianyu Wang & Liang Wang & Yuelong Yan & Ling Xia & Rakesh Bam & Zhifen Yang & Hyemin Lee & Takao Iwawaki & Boyi Gan & Albert C. Koong, 2024. "IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    20. Chuanyu Tang & Cheng He & Decheng Wang & Jie Guo & Xiangyi Yin & Hanjie Ye & Lei Wu & Yuling Zhang & Silue Zeng & Xiaojun Zeng & Chengbo Liu & Jingqin Chen & Chihua Fang, 2025. "Co-delivery of sorafenib and an FSP1 inhibitor triggers dual ferroptosis in tumor cells and immunosuppressive macrophages for enhanced immunotherapy in mouse models of hepatocellular carcinoma," Nature Communications, Nature, vol. 16(1), pages 1-23, 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:16:y:2025:i:1:d:10.1038_s41467-025-65025-2. 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.